View source for Serpin

{{short description|Superfamily of proteins with similar structures and diverse functions}}
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{{Use dmy dates|date=March 2016}}
{{Infobox protein family
| Symbol = Serpin, SERPIN ([https://www.genenames.org/cgi-bin/genefamilies/ root symbol] of family)
| Name = Serpin (serine protease inhibitor)
| image = serpin_(stressed).png
| width = 
| caption = A serpin (white) with its 'reactive centre loop' (blue) bound to a [[protease]] (grey). Once the protease attempts [[enzyme catalysis|catalysis]] it will be [[irreversible inhibition|irreversibly inhibited]]. ({{PDB|1K9O}})
| Pfam= PF00079
| InterPro= IPR000215
| SMART= 
| Prosite = PDOC00256
| SCOP = 1hle
| TCDB = 
| OPM family= 
| OPM protein= 
| CDD = cd00172
| PDB= 
{{PDB3|1m37}}A:1-378     {{PDB3|1hle}}B:349-379   {{PDB3|1jrr}}A:1-415
{{PDB3|1by7}}A:1-415     {{PDB3|1ova}}A:1-385     {{PDB3|1uhg}}A:1-385
{{PDB3|1jti}}B:1-385     {{PDB3|1att}}B:77-433    {{PDB3|1nq9}}L:76-461
{{PDB3|1oyh}}I:76-461    {{PDB3|1e03}}L:76-461    {{PDB3|1e05}}I:76-461
{{PDB3|1br8}}L:76-461    {{PDB3|1r1l}}L:76-461    {{PDB3|1lk6}}L:76-461
{{PDB3|1ant}}L:76-461    {{PDB3|2beh}}L:76-461    {{PDB3|1dzh}}L:76-461
{{PDB3|1ath}}A:78-461    {{PDB3|1tb6}}I:76-461    {{PDB3|2ant}}I:76-461p
{{PDB3|1dzg}}I:76-461    {{PDB3|1azx}}L:76-461    {{PDB3|1jvq}}I:76-461
{{PDB3|1sr5}}A:76-461    {{PDB3|1e04}}I:76-461    {{PDB3|1xqg}}A:1-375
{{PDB3|1xu8}}B:1-375     {{PDB3|1wz9}}B:1-375     {{PDB3|1xqj}}A:1-375
{{PDB3|1c8o}}A:1-300     {{PDB3|1m93}}A:1-55      {{PDB3|1f0c}}A:1-305
{{PDB3|1k9o}}I:18-392    {{PDB3|1sek}} :18-369    {{PDB3|1atu}} :45-415
{{PDB3|1ezx}}B:383-415   {{PDB3|8api}}A:43-382    {{PDB3|1qmb}}A:49-376
{{PDB3|1iz2}}A:43-415    {{PDB3|1oo8}}A:43-415    {{PDB3|1d5s}}B:378-415
{{PDB3|7api}}A:44-382    {{PDB3|1qlp}}A:43-415    {{PDB3|1oph}}A:43-415
{{PDB3|1kct}} :44-415    {{PDB3|2d26}}A:43-382    {{PDB3|9api}}B:383-415
{{PDB3|1psi}} :47-415    {{PDB3|1hp7}}A:43-415    {{PDB3|3caa}}A:50-383
{{PDB3|1qmn}}A:43-420    {{PDB3|4caa}}B:390-420   {{PDB3|2ach}}A:47-383
{{PDB3|1as4}}A:48-383    {{PDB3|1yxa}}B:42-417    {{PDB3|1lq8}}F:376-406
{{PDB3|2pai}}B:374-406   {{PDB3|1pai}}B:374-406   {{PDB3|1jmo}}A:119-496
{{PDB3|1jmj}}A:119-496   {{PDB3|1oc0}}A:25-402    {{PDB3|1dvn}}A:25-402
{{PDB3|1b3k}}D:25-402    {{PDB3|1dvm}}D:25-402    {{PDB3|1a7c}}A:25-402
{{PDB3|1c5g}}A:25-402    {{PDB3|1db2}}B:26-402    {{PDB3|9pai}}A:25-402
{{PDB3|1lj5}}A:25-402    {{PDB3|1m6q}}A:138-498   {{PDB3|1jjo}}D:101-361
{{PDB3|1imv}}A:49-415
}}

'''Serpins''' are a [[Protein superfamily|superfamily]] of [[protein]]s with similar structures that were first identified for their [[Protease inhibitor (biology)|protease inhibition]] activity and are found in all [[kingdom (biology)|kingdoms of life]].<ref name="Silverman_2001" /><ref>{{cite journal | vauthors = Spence MA, Mortimer MD, Buckle AM, Minh BQ, Jackson CJ | title = A Comprehensive Phylogenetic Analysis of the Serpin Superfamily | journal = Molecular Biology and Evolution | volume = 38 | issue = 7 | pages = 2915–2929 | date = June 2021 | pmid = 33744972 | pmc = 8233489 | doi = 10.1093/molbev/msab081 | veditors = Echave J }}</ref> The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like [[serine protease]]s ('''ser'''ine '''p'''rotease '''in'''hibitors).<ref>{{cite book| vauthors = Carrell RW, Boswell DR |chapter=Serpins: the superfamily of plasma serine proteinase inhibitors|title=Proteinase Inhibitors|publisher=[[Elsevier Science Publishers BV]]|year=1986|isbn=0-444-80763-2| series = Research monographs in cell and tissue physiology | volume = 12 | veditors = Barrett AJ, Salvesen G |location=Amsterdam|pages=403–420|language=English}}</ref><ref name="Silverman_2010">{{cite journal | vauthors = Silverman GA, Whisstock JC, Bottomley SP, Huntington JA, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Bird PI | title = Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems | journal = The Journal of Biological Chemistry | volume = 285 | issue = 32 | pages = 24299–24305 | date = August 2010 | pmid = 20498369 | pmc = 2915665 | doi = 10.1074/jbc.R110.112771 | doi-access = free }}</ref><ref name="Whisstock_2010">{{cite journal | vauthors = Whisstock JC, Silverman GA, Bird PI, Bottomley SP, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Huntington JA | title = Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions | journal = The Journal of Biological Chemistry | volume = 285 | issue = 32 | pages = 24307–24312 | date = August 2010 | pmid = 20498368 | pmc = 2915666 | doi = 10.1074/jbc.R110.141408 | doi-access = free }}</ref> They are notable for their unusual mechanism of action, in which they [[Irreversible inhibition|irreversibly inhibit]] their target [[protease]] by undergoing a large [[conformational change]] to disrupt the target's [[active site]].<ref name="Huntington_2000">{{cite journal | vauthors = Huntington JA, Read RJ, Carrell RW | title = Structure of a serpin-protease complex shows inhibition by deformation | journal = Nature | volume = 407 | issue = 6806 | pages = 923–926 | date = October 2000 | pmid = 11057674 | doi = 10.1038/35038119 | s2cid = 205009937 | bibcode = 2000Natur.407..923H }}</ref><ref name="Gettins_2002">{{cite journal | vauthors = Gettins PG | title = Serpin structure, mechanism, and function | journal = Chemical Reviews | volume = 102 | issue = 12 | pages = 4751–4804 | date = December 2002 | pmid = 12475206 | doi = 10.1021/cr010170 }}</ref> This contrasts with the more common [[Competitive inhibition|competitive]] mechanism for protease inhibitors that bind to and block access to the protease active site.<ref name="Whisstock_2006">{{cite journal | vauthors = Whisstock JC, Bottomley SP | title = Molecular gymnastics: serpin structure, folding and misfolding | journal = Current Opinion in Structural Biology | volume = 16 | issue = 6 | pages = 761–768 | date = December 2006 | pmid = 17079131 | doi = 10.1016/j.sbi.2006.10.005 }}</ref><ref name="Law_2006"/>

Protease inhibition by serpins controls an array of biological processes, including [[coagulation]] and [[inflammation]], and consequently these proteins are the target of [[medical research]].<ref name="Stein_1995">{{cite journal | vauthors = Stein PE, Carrell RW | title = What do dysfunctional serpins tell us about molecular mobility and disease? | journal = Nature Structural Biology | volume = 2 | issue = 2 | pages = 96–113 | date = February 1995 | pmid = 7749926 | doi = 10.1038/nsb0295-96 | s2cid = 21223825 }}</ref> Their unique conformational change also makes them of interest to the [[structural biology]] and [[protein folding]] research communities.<ref name="Gettins_2002"/><ref name="Whisstock_2006" /> The conformational-change mechanism confers certain advantages, but it also has drawbacks: serpins are vulnerable to [[mutations]] that can result in serpinopathies such as [[Proteopathy|protein misfolding]] and the formation of inactive long-chain [[polymer]]s.<ref name="Janciauskiene_2011">{{cite journal | vauthors = Janciauskiene SM, Bals R, Koczulla R, Vogelmeier C, Köhnlein T, Welte T | title = The discovery of α1-antitrypsin and its role in health and disease | journal = Respiratory Medicine | volume = 105 | issue = 8 | pages = 1129–1139 | date = August 2011 | pmid = 21367592 | doi = 10.1016/j.rmed.2011.02.002 | doi-access = free }}</ref><ref name="Carrell_1997" /> Serpin [[polymerisation]] not only reduces the amount of active inhibitor, but also leads to accumulation of the polymers, causing [[cell death]] and [[organ dysfunction|organ failure]].<ref name="Stein_1995"/>

Although most serpins control [[proteolysis|proteolytic]] cascades, some proteins with a serpin structure are not [[enzyme inhibitor]]s, but instead perform diverse functions such as [[storage protein|storage]] (as in [[egg white]]—[[ovalbumin]]), transport as in hormone [[carriage proteins]] ([[thyroxine-binding globulin]], [[transcortin|cortisol-binding globulin]]) and [[molecular chaperone|molecular chaperoning]] ([[HSP47]]).<ref name="Law_2006"/> The term ''serpin'' is used to describe these members as well, despite their non-inhibitory function, since they are evolutionarily related.<ref name="Silverman_2001" />

== History ==
Protease inhibitory activity in blood plasma was first reported in the late 1800s,<ref>{{cite journal | vauthors = Fermi C, Pernossi L | title = Untersuchungen uber die enzyme, Vergleichende Studie | trans-title = Studies on the enzyme, Comparative study | language = de | journal = Zeitschrift für Hygiene und Infektionskrankheiten | date = December 1894 | issue = 18 | pages = 83–89 | doi = 10.1007/BF02216836 | s2cid = 24373770 | url = https://ia800708.us.archive.org/view_archive.php?archive=/22/items/crossref-pre-1909-scholarly-works/10.1007%252Fbf02214664.zip&file=10.1007%252Fbf02216836.pdf }}{{Dead link|date=October 2025 |bot=InternetArchiveBot }}</ref> but it was not until the 1950s that the serpins [[antithrombin]] and [[alpha 1-antitrypsin]] were isolated,<ref>{{cite journal | vauthors = Schultze HU, Göllner I, Heide K, Schönenberger M, Schwick G | s2cid = 95960716 | title = Zur Kenntnis der alpha-globulin des menschlichen normal serums | trans-title = For knowledge of the alpha - globulin of human normal serums | language = de | journal = Zeitschrift für Naturforschung B | date = August 1955 | volume = 10 | issue = 8 | page = 463 | doi = 10.1515/znb-1955-0810 | doi-access = free }}</ref> with the subsequent recognition of their close family homology in 1979.<ref>{{cite book| vauthors = Petersen TE, Dudeck-Wojciechowska G, Sottrup-Jensen L, Magnusson S | chapter = Primary structure of antithrombin III (heparin cofactor): partial homology between alpha-1-antitrypsin and antithrombin III| title =The Physiological Inhibitors of Coagulation and Fibrinolysis|publisher=[[Elsevier]]|year=1979| veditors = Collen D, Wiman B, Verstraete M |location=Amsterdam|pages=43–54}}</ref><ref>{{cite journal | vauthors = Carrell R, Owen M, Brennan S, Vaughan L | title = Carboxy terminal fragment of human alpha-1-antitrypsin from hydroxylamine cleavage: homology with antithrombin III | journal = Biochemical and Biophysical Research Communications | volume = 91 | issue = 3 | pages = 1032–1037 | date = December 1979 | pmid = 316698 | doi = 10.1016/0006-291X(79)91983-1 | bibcode = 1979BBRC...91.1032C }}</ref> That they belonged to a new protein family became apparent on their further alignment with the non-inhibitory egg-white protein [[ovalbumin]], to give what was initially called the ''alpha1-antitrypsin-antithrombin III-ovalbumin [[Protein superfamily|superfamily]] of serine proteinase inhibitors,''<ref>{{cite journal | vauthors = Hunt LT, Dayhoff MO | title = A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor | journal = Biochemical and Biophysical Research Communications | volume = 95 | issue = 2 | pages = 864–871 | date = July 1980 | pmid = 6968211 | doi = 10.1016/0006-291X(80)90867-0 }}</ref> but was subsequently succinctly renamed as the Serpins.<ref>{{cite journal | vauthors = Carrell RW, Jeppsson JO, Laurell CB, Brennan SO, Owen MC, Vaughan L, Boswell DR | title = Structure and variation of human alpha 1-antitrypsin | journal = Nature | volume = 298 | issue = 5872 | pages = 329–334 | date = July 1982 | pmc = 7172600 | doi = 10.1016/0968-0004(85)90011-8 | pmid = 7045697 }}</ref> The initial characterisation of the new family centred on [[Alpha-1 antitrypsin|alpha1-antitrypsin]], a serpin present in high concentration in blood plasma, the common [[genetic disorder]] of which was shown to cause a predisposition to the lung disease [[emphysema]]<ref name="Laurell_2013">{{cite journal | vauthors = Laurell CB, Eriksson S | title = The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. 1963 | journal = Copd | volume = 10 | issue = Suppl 1 | pages = 3–8 | date = March 2013 | pmid = 23527532 | doi = 10.3109/15412555.2013.771956 | s2cid = 36366089 | doi-access = free }}</ref> and to liver [[cirrhosis]].<ref>{{cite journal | vauthors = Sharp HL, Bridges RA, Krivit W, Freier EF | title = Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder | journal = The Journal of Laboratory and Clinical Medicine | volume = 73 | issue = 6 | pages = 934–939 | date = June 1969 | pmid = 4182334 }}</ref> The identification of the S and Z mutations<ref>{{cite journal | vauthors =  | title = Alpha-1-antitrypsin: molecular abnormality of S variant | journal = British Medical Journal | volume = 1 | issue = 6002 | pages = 130–131 | date = January 1976 | pmid = 1082356 | pmc = 1638590 | doi = 10.1136/bmj.1.6002.130-a }}</ref><ref>{{cite journal | vauthors = Jeppsson JO | title = Amino acid substitution Glu leads to Lys alpha1-antitrypsin PiZ | journal = FEBS Letters | volume = 65 | issue = 2 | pages = 195–197 | date = June 1976 | pmid = 1084290 | doi = 10.1016/0014-5793(76)80478-4 | s2cid = 84576569 | doi-access = free }}</ref> responsible for the genetic deficiency and the subsequent sequence alignments of alpha1-antitrypsin and antithrombin in 1982 led to the recognition of the close homologies of the active sites of the two proteins,<ref>{{cite journal | vauthors = Carrell RW, Jeppsson JO, Laurell CB, Brennan SO, Owen MC, Vaughan L, Boswell DR | title = Structure and variation of human alpha 1-antitrypsin | journal = Nature | volume = 298 | issue = 5872 | pages = 329–334 | date = July 1982 | pmid = 7045697 | doi = 10.1038/298329a0 | bibcode = 1982Natur.298..329C | s2cid = 11904305 }}</ref><ref>{{cite journal | vauthors = Carrell RW, Boswell DR, Brennan SO, Owen MC | title = Active site of alpha 1-antitrypsin: homologous site in antithrombin-III | journal = Biochemical and Biophysical Research Communications | volume = 93 | issue = 2 | pages = 399–402 | date = March 1980 | pmid = 6966929 | doi = 10.1016/0006-291X(80)91090-6 }}</ref>  centred on a methionine<ref>{{cite journal | vauthors = Johnson D, Travis J | title = Structural evidence for methionine at the reactive site of human alpha-1-proteinase inhibitor | journal = The Journal of Biological Chemistry | volume = 253 | issue = 20 | pages = 7142–7144 | date = October 1978 | doi = 10.1016/S0021-9258(17)34475-7 | pmid = 701239 | doi-access = free }}</ref> in alpha1-antitrypsin as an inhibitor of tissue elastase and on arginine in antithrombin<ref>{{cite journal | vauthors = Jörnvall H, Fish WW, Björk I | title = The thrombin cleavage site in bovine antithrombin | journal = FEBS Letters | volume = 106 | issue = 2 | pages = 358–362 | date = October 1979 | pmid = 499520 | doi = 10.1016/0014-5793(79)80532-3 | s2cid = 32540550 | doi-access = free | bibcode = 1979FEBSL.106..358J }}</ref> as an inhibitor of thrombin.<ref>{{cite journal | vauthors = Egeberg O | title =  Inherited antithrombin deficiency causing thrombophilia | journal = Thrombosis et Diathesis Haemorrhagica | volume = 13 | issue = 2 | pages = 516–530 | date = June 1965 | pmid = 14347873 | doi = 10.1055/s-0038-1656297 | s2cid = 42594050 }}</ref>

The critical role of the active centre residue in determining the specificity of inhibition of serpins was unequivocally confirmed by the finding that a natural mutation of the active centre methionine  in alpha1-antitrypsin to an arginine, as in antithrombin, resulted in a severe bleeding disorder.<ref name="Mutation of antitrypsin to antithro">{{cite journal | vauthors = Owen MC, Brennan SO, Lewis JH, Carrell RW | title = Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder | journal = The New England Journal of Medicine | volume = 309 | issue = 12 | pages = 694–698 | date = September 1983 | pmid = 6604220 | doi = 10.1056/NEJM198309223091203 }}</ref> This active-centre specificity of inhibition was also evident in the many other families of protease inhibitors<ref name="Gettins_2002" /> but the serpins differed from them in being much larger proteins and also in possessing what was soon apparent as an inherent ability to undergo a change in shape. The nature of this conformational change was revealed with the determination in 1984 of the first crystal [[Biomolecular structure|structure]] of a serpin, that of post-cleavage alpha1-antitrypsin.<ref name="Huber_1984">{{cite journal | vauthors = Loebermann H, Tokuoka R, Deisenhofer J, Huber R | title = Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function | journal = Journal of Molecular Biology | volume = 177 | issue = 3 | pages = 531–557 | date = August 1984 | pmid = 6332197 | doi = 10.1016/0022-2836(84)90298-5 }}</ref> This together with the subsequent solving of the structure of native (uncleaved) ovalbumin<ref name="Stein_1990">{{cite journal | vauthors = Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW | title = Crystal structure of ovalbumin as a model for the reactive centre of serpins | journal = Nature | volume = 347 | issue = 6288 | pages = 99–102 | date = September 1990 | pmid = 2395463 | doi = 10.1038/347099a0 | bibcode = 1990Natur.347...99S | s2cid = 4342263 }}</ref> indicated that the inhibitory mechanism of the  serpins involved a remarkable conformational shift,  with the movement of the exposed peptide loop containing the reactive site and its incorporation as a middle strand in the main beta-pleated sheet that characterises the serpin molecule.<ref name="Carrell_1991">{{cite journal | vauthors = Carrell RW, Evans DL, Stein PE | title = Mobile reactive centre of serpins and the control of thrombosis | journal = Nature | volume = 353 | issue = 6344 | pages = 576–578 | date = October 1991 | pmid = 1922367 | doi = 10.1038/353576a0 | bibcode = 1991Natur.353..576C | s2cid = 4361304 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mottonen J, Strand A, Symersky J, Sweet RM, Danley DE, Geoghegan KF, Gerard RD, Goldsmith EJ | title = Structural basis of latency in plasminogen activator inhibitor-1 | journal = Nature | volume = 355 | issue = 6357 | pages = 270–273 | date = January 1992 | pmid = 1731226 | doi = 10.1038/355270a0 | bibcode = 1992Natur.355..270M | s2cid = 4365370 }}</ref> Early evidence of the essential role of this loop movement in the inhibitory mechanism came from the finding that even minor aberrations in the amino acid residues that form the hinge of the movement in antithrombin resulted in thrombotic disease.<ref name="Carrell_1991" /><ref>{{cite journal | vauthors = Austin RC, Rachubinski RA, Ofosu FA, Blajchman MA | title = Antithrombin-III-Hamilton, Ala 382 to Thr: an antithrombin-III variant that acts as a substrate but not an inhibitor of alpha-thrombin and factor Xa | journal = Blood | volume = 77 | issue = 10 | pages = 2185–2189 | date = May 1991 | doi = 10.1182/blood.V77.10.2185.2185 | pmid = 2029579 | doi-access = free }}</ref> Ultimate confirmation of the linked displacement of the target protease by this loop movement was provided  in 2000 by the structure of the post-inhibitory complex of alpha1-antitrypsin with trypsin,<ref name="Huntington_2000" /> showing how the displacement results in the deformation and inactivation of the attached protease. Subsequent structural studies have revealed an additional advantage of the conformational mechanism<ref name="Huntington_2006" /> in allowing the subtle modulation of inhibitory activity, as notably seen at tissue level<ref>{{cite journal | vauthors = Carrell RW, Read RJ | title = How serpins transport hormones and regulate their release | journal = Seminars in Cell & Developmental Biology | volume = 62 | pages = 133–141 | date = February 2017 | pmid = 28027946 | doi = 10.1016/j.semcdb.2016.12.007 | url = https://www.repository.cam.ac.uk/handle/1810/263922 }}</ref> with the functionally diverse serpins in human plasma.

Over 1000&nbsp;serpins have now been identified, including 36&nbsp;human proteins, as well as molecules in all [[kingdom (biology)|kingdom]]s of life—[[animals]], [[plants]], [[fungi]], [[bacteria]], and [[archaea]]—and some [[Poxviridae|viruses]].<ref name="Irving_2000" /><ref name="Irving_2002" /><ref name="Steenbakkers_2008">{{cite journal | vauthors = Steenbakkers PJ, Irving JA, Harhangi HR, Swinkels WJ, Akhmanova A, Dijkerman R, Jetten MS, van der Drift C, Whisstock JC, Op den Camp HJ | title = A serpin in the cellulosome of the anaerobic fungus Piromyces sp. strain E2 | journal = Mycological Research | volume = 112 | issue = Pt 8 | pages = 999–1006 | date = August 2008 | pmid = 18539447 | doi = 10.1016/j.mycres.2008.01.021 | url = https://zenodo.org/record/852424 | hdl = 2066/72679 | hdl-access = free }}</ref> The central feature of all is a tightly conserved framework, which allows the precise alignment of their key structural and functional components based on the template structure of alpha1-antitrypsin.<ref>{{cite journal | vauthors = Huber R, Carrell RW | title = Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins | journal = Biochemistry | volume = 28 | issue = 23 | pages = 8951–8966 | date = November 1989 | pmid = 2690952 | doi = 10.1021/bi00449a001 }}</ref>  In the 2000s, a systematic nomenclature was introduced in order to categorise members of the serpin superfamily based on their evolutionary relationships.<ref name="Silverman_2001">{{cite journal | vauthors = Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC | title = The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature | journal = The Journal of Biological Chemistry | volume = 276 | issue = 36 | pages = 33293–33296 | date = September 2001 | pmid = 11435447 | doi = 10.1074/jbc.R100016200 | doi-access = free }}</ref> Serpins are therefore the largest and most diverse superfamily of protease inhibitors.<ref name="Rawlings_2004">{{cite journal | vauthors = Rawlings ND, Tolle DP, Barrett AJ | title = Evolutionary families of peptidase inhibitors | journal = The Biochemical Journal | volume = 378 | issue = Pt 3 | pages = 705–716 | date = March 2004 | pmid = 14705960 | pmc = 1224039 | doi = 10.1042/BJ20031825 }}</ref>

== Activity ==
[[File:Serpin and protease.png|thumb|A [[protease]] (grey) bound to a serpin reactive centre loop (RCL, blue). When the protease's [[catalytic triad]] (red) [[Proteolysis|cleaves]] the RCL, it becomes trapped in an [[Irreversible inhibition|inactive conformation]]. ({{PDB|1K9O}})|alt=Diagram of a serpin and protease]]
Most serpins are [[protease]] inhibitors, targeting extracellular, [[chymotrypsin]]-like [[serine protease]]s. These proteases possess a [[nucleophile|nucleophilic]] [[serine]] residue in a [[catalytic triad]] in their [[active site]]. Examples include [[thrombin]], [[trypsin]], and [[human neutrophil elastase]].<ref>{{cite journal | vauthors = Barrett AJ, Rawlings ND | title = Families and clans of serine peptidases | journal = Archives of Biochemistry and Biophysics | volume = 318 | issue = 2 | pages = 247–250 | date = April 1995 | pmid = 7733651 | doi = 10.1006/abbi.1995.1227 }}</ref> Serpins act as [[Irreversible inhibition|irreversible]], [[suicide inhibitor]]s by trapping an intermediate of the protease's catalytic mechanism.<ref name="Huntington_2000" />

Some serpins inhibit other protease classes, typically [[cysteine protease]]s, and are termed "cross-class inhibitors". These enzymes differ from serine proteases in that they use a nucleophilic [[cysteine]] residue, rather than a [[serine]], in their active site.<ref>{{cite journal | vauthors = Barrett AJ, Rawlings ND | title = Evolutionary lines of cysteine peptidases | journal = Biological Chemistry | volume = 382 | issue = 5 | pages = 727–733 | date = May 2001 | pmid = 11517925 | doi = 10.1515/BC.2001.088 | s2cid = 37306786 | doi-access = free }}</ref> Nonetheless, the enzymatic chemistry is similar, and the mechanism of inhibition by serpins is the same for both classes of protease.<ref>{{cite journal | vauthors = Irving JA, Pike RN, Dai W, Brömme D, Worrall DM, Silverman GA, Coetzer TH, Dennison C, Bottomley SP, Whisstock JC | title = Evidence that serpin architecture intrinsically supports papain-like cysteine protease inhibition: engineering alpha(1)-antitrypsin to inhibit cathepsin proteases | journal = Biochemistry | volume = 41 | issue = 15 | pages = 4998–5004 | date = April 2002 | pmid = 11939796 | doi = 10.1021/bi0159985 }}</ref> Examples of cross-class inhibitory serpins include [[SERPINB4|serpin B4]] a [[squamous cell carcinoma]] antigen&nbsp;1 (SCCA-1) and the avian serpin [[myeloid and erythroid nuclear termination stage-specific protein]] (MENT), which both inhibit [[papain-like protease|papain-like]] [[cysteine protease]]s.<ref name="Schick_1998">{{cite journal | vauthors = Schick C, Brömme D, Bartuski AJ, Uemura Y, Schechter NM, Silverman GA | title = The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13465–13470 | date = November 1998 | pmid = 9811823 | pmc = 24842 | doi = 10.1073/pnas.95.23.13465 | doi-access = free | bibcode = 1998PNAS...9513465S }}</ref><ref name="McGowan_2006">{{cite journal | vauthors = McGowan S, Buckle AM, Irving JA, Ong PC, Bashtannyk-Puhalovich TA, Kan WT, Henderson KN, Bulynko YA, Popova EY, Smith AI, Bottomley SP, Rossjohn J, Grigoryev SA, Pike RN, Whisstock JC | title = X-ray crystal structure of MENT: evidence for functional loop-sheet polymers in chromatin condensation | journal = The EMBO Journal | volume = 25 | issue = 13 | pages = 3144–3155 | date = July 2006 | pmid = 16810322 | pmc = 1500978 | doi = 10.1038/sj.emboj.7601201 }}</ref><ref>{{cite journal | vauthors = Ong PC, McGowan S, Pearce MC, Irving JA, Kan WT, Grigoryev SA, Turk B, Silverman GA, Brix K, Bottomley SP, Whisstock JC, Pike RN | title = DNA accelerates the inhibition of human cathepsin V by serpins | journal = The Journal of Biological Chemistry | volume = 282 | issue = 51 | pages = 36980–36986 | date = December 2007 | pmid = 17923478 | doi = 10.1074/jbc.M706991200 | doi-access = free }}</ref>

==Biological function and localization==

=== Protease inhibition ===
Approximately two-thirds of human serpins perform extracellular roles, inhibiting proteases in the bloodstream in order to modulate their activities. For example, extracellular serpins regulate the proteolytic cascades central to [[blood clotting]] (antithrombin), the [[Inflammation|inflammatory]] and [[immune responses]] (antitrypsin, [[alpha 1-antichymotrypsin|antichymotrypsin]], and [[C1-inhibitor]]) and tissue remodelling [[Plasminogen activator inhibitor-1|(PAI-1)]].<ref name="Law_2006"/> By inhibiting [[signalling cascade]] proteases, they can also affect [[Developmental biology|development]].<ref name="Acosta 1146–1158">{{cite journal | vauthors = Acosta H, Iliev D, Grahn TH, Gouignard N, Maccarana M, Griesbach J, Herzmann S, Sagha M, Climent M, Pera EM | title = The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation | journal = Development | volume = 142 | issue = 6 | pages = 1146–1158 | date = March 2015 | pmid = 25758225 | doi = 10.1242/dev.113886 | doi-access = free }}</ref><ref name="Hashimoto 945–950">{{cite journal | vauthors = Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D | title = Spatial regulation of developmental signaling by a serpin | journal = Developmental Cell | volume = 5 | issue = 6 | pages = 945–950 | date = December 2003 | pmid = 14667416 | doi = 10.1016/S1534-5807(03)00338-1 | doi-access = free }}</ref> The table of human serpins (below) provides examples of the range of functions performed by human serpin, as well as some of the diseases that result from serpin deficiency.

The protease targets of intracellular inhibitory serpins have been difficult to identify, since many of these molecules appear to perform overlapping roles. Further, many human serpins lack precise functional equivalents in model organisms such as the mouse. Nevertheless, an important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell.<ref>{{cite journal | vauthors = Bird PI | title = Regulation of pro-apoptotic leucocyte granule serine proteinases by intracellular serpins | journal = Immunology and Cell Biology | volume = 77 | issue = 1 | pages = 47–57 | date = February 1999 | pmid = 10101686 | doi = 10.1046/j.1440-1711.1999.00787.x | s2cid = 44268106 }}</ref> For example, one of the best-characterised human intracellular serpins is [[SERPINB9|Serpin B9]], which inhibits the [[cytotoxic]] [[granule (cell biology)|granule]] protease [[granzyme B]]. In doing so, Serpin B9 may protect against inadvertent release of granzyme B and premature or unwanted activation of [[apoptosis|cell death]] pathways.<ref>{{cite journal | vauthors = Bird CH, Sutton VR, Sun J, Hirst CE, Novak A, Kumar S, Trapani JA, Bird PI | title = Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway | journal = Molecular and Cellular Biology | volume = 18 | issue = 11 | pages = 6387–6398 | date = November 1998 | pmid = 9774654 | pmc = 109224 | doi = 10.1128/mcb.18.11.6387 }}</ref>

Some [[virus]]es use serpins to disrupt protease functions in their host. The [[cowpox]] [[viral protein|viral serpin]] CrmA (cytokine response modifier A) is used in order to avoid inflammatory and [[apoptosis|apoptotic]] responses of infected host cells. CrmA increases infectivity by suppressing its host's inflammatory response through inhibition of [[Interleukin 1 family|IL-1]] and [[Interleukin 18|IL-18]] processing by the cysteine protease [[caspase]]-1.<ref>{{cite journal | vauthors = Ray CA, Black RA, Kronheim SR, Greenstreet TA, Sleath PR, Salvesen GS, Pickup DJ | title = Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme | journal = Cell | volume = 69 | issue = 4 | pages = 597–604 | date = May 1992 | pmid = 1339309 | doi = 10.1016/0092-8674(92)90223-Y | s2cid = 7398844 }}</ref> In [[eukaryotes]], a plant serpin inhibits both [[metacaspase]]s<ref name="Vercammen_2006">{{cite journal | vauthors = Vercammen D, Belenghi B, van de Cotte B, Beunens T, Gavigan JA, De Rycke R, Brackenier A, Inzé D, Harris JL, Van Breusegem F | title = Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9 | journal = Journal of Molecular Biology | volume = 364 | issue = 4 | pages = 625–636 | date = December 2006 | pmid = 17028019 | doi = 10.1016/j.jmb.2006.09.010 }}</ref> and a papain-like cysteine protease.<ref name="Lampl_2010">{{cite journal | vauthors = Lampl N, Budai-Hadrian O, Davydov O, Joss TV, Harrop SJ, Curmi PM, Roberts TH, Fluhr R | title = Arabidopsis AtSerpin1, crystal structure and in vivo interaction with its target protease RESPONSIVE TO DESICCATION-21 (RD21) | journal = The Journal of Biological Chemistry | volume = 285 | issue = 18 | pages = 13550–13560 | date = April 2010 | pmid = 20181955 | pmc = 2859516 | doi = 10.1074/jbc.M109.095075 | doi-access = free }}</ref>

=== Non-inhibitory roles ===
Non-inhibitory extracellular serpins also perform a wide array of important roles. [[Thyroxine-binding globulin]] and [[transcortin]] transport the hormones [[thyroxine]] and [[cortisol]], respectively.<ref name="cbg">{{cite journal | vauthors = Klieber MA, Underhill C, Hammond GL, Muller YA | title = Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release | journal = The Journal of Biological Chemistry | volume = 282 | issue = 40 | pages = 29594–29603 | date = October 2007 | pmid = 17644521 | doi = 10.1074/jbc.M705014200 | doi-access = free }}</ref><ref name="Zhou_2006"/> The non-inhibitory serpin [[ovalbumin]] is the most abundant protein in [[egg white]]. Its exact function is unknown, but it is thought to be a [[storage protein]] for the [[prenatal development|developing foetus]].<ref>{{cite journal | vauthors = Huntington JA, Stein PE | title = Structure and properties of ovalbumin | journal = Journal of Chromatography. B, Biomedical Sciences and Applications | volume = 756 | issue = 1–2 | pages = 189–198 | date = May 2001 | pmid = 11419711 | doi = 10.1016/S0378-4347(01)00108-6 }}</ref> [[Heat shock protein 47|Heat shock serpin 47]] is a [[Chaperone (protein)|chaperone]], essential for proper [[folding (chemistry)|folding]] of [[collagen]]. It acts by stabilising collagen's [[Collagen|triple helix]] whilst it is being processed in the [[endoplasmic reticulum]].<ref name="Mala_2010">{{cite journal | vauthors = Mala JG, Rose C | title = Interactions of heat shock protein 47 with collagen and the stress response: an unconventional chaperone model? | journal = Life Sciences | volume = 87 | issue = 19–22 | pages = 579–586 | date = November 2010 | pmid = 20888348 | doi = 10.1016/j.lfs.2010.09.024 }}</ref>

Some serpins are both protease inhibitors and perform additional roles. For example, the nuclear cysteine protease inhibitor [[myeloid and erythroid nuclear termination stage specific protein|MENT]], in [[bird]]s also acts as a [[chromatin remodeling|chromatin remodelling]] molecule in a bird's [[red blood cell]]s.<ref name="McGowan_2006"/><ref>{{cite journal | vauthors = Grigoryev SA, Bednar J, Woodcock CL | title = MENT, a heterochromatin protein that mediates higher order chromatin folding, is a new serpin family member | journal = The Journal of Biological Chemistry | volume = 274 | issue = 9 | pages = 5626–5636 | date = February 1999 | pmid = 10026180 | doi = 10.1074/jbc.274.9.5626 | doi-access = free }}</ref>

== Structure ==
[[Image:Serpin_equilibrium.png|thumb|right|450px|The native state of serpins is an equilibrium between a fully stressed state (left) and a partially relaxed state (right). The five-stranded A-sheet (light blue) contains two functionally important regions for the serpin's mechanism, the breach and the shutter. The reactive centre loop (RCL, blue) exists in a dynamic equilibrium between the fully exposed conformation (left) and a conformation where it is partially inserted into the breach of the A-sheet (right).({{PDB|1QLP|1YXA}})<ref>{{cite journal | vauthors = Elliott PR, Lomas DA, Carrell RW, Abrahams JP | title = Inhibitory conformation of the reactive loop of alpha 1-antitrypsin | journal = Nature Structural Biology | volume = 3 | issue = 8 | pages = 676–681 | date = August 1996 | pmid = 8756325 | doi = 10.1038/nsb0896-676 | s2cid = 22976014 }}</ref><ref name="Horvath_2005">{{cite journal | vauthors = Horvath AJ, Irving JA, Rossjohn J, Law RH, Bottomley SP, Quinsey NS, Pike RN, Coughlin PB, Whisstock JC | title = The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins | journal = The Journal of Biological Chemistry | volume = 280 | issue = 52 | pages = 43168–43178 | date = December 2005 | pmid = 16141197 | doi = 10.1074/jbc.M505598200 | doi-access = free }}</ref>|alt=Diagram of serpin states]]

All serpins share a common [[Protein tertiary structure|structure]] (or fold), despite their varied functions. All typically have three [[beta sheet|β-sheets]] (named A, B and C) and eight or nine [[alpha helix|α-helices]] (named hA–hI).<ref name="Huber_1984" /><ref name="Stein_1990"/> The most significant regions to serpin function are the A-sheet and the reactive centre loop (RCL). The A-sheet includes two [[β strands|β-strands]] that are in a parallel orientation with a region between them called the 'shutter', and upper region called the 'breach'. The RCL forms the initial interaction with the target protease in inhibitory molecules. Structures have been solved showing the RCL either fully exposed or partially inserted into the A-sheet, and serpins are thought to be in [[dynamic equilibrium]] between these two states.<ref name="Whisstock_2006" /> The RCL also only makes temporary interactions with the rest of the structure, and is therefore highly flexible and exposed to the solvent.<ref name="Whisstock_2006" />

The serpin structures that have been determined cover several different conformations, which has been necessary for the understanding of their multiple-step mechanism of action. [[X-ray crystallography|Structural biology]] has therefore played a central role in the understanding of serpin function and biology.<ref name="Whisstock_2006"/>

==Conformational change and inhibitory mechanism==
Inhibitory serpins do not inhibit their target proteases by the typical [[Competitive inhibition|competitive]] (''lock-and-key'') mechanism used by most small [[protease inhibitor (biology)|protease inhibitors]] (e.g. [[Kunitz-type protease inhibitor|Kunitz-type inhibitor]]s). Instead, serpins use an unusual [[conformational change]], which disrupts the structure of the protease and prevents it from completing catalysis. The conformational change involves the RCL moving to the opposite end of the protein and inserting into β-sheet A, forming an extra [[Beta sheet|antiparallel]] β-strand. This converts the serpin from a stressed state, to a lower-energy relaxed state (S to R transition).<ref name="Gettins_2002"/><ref name="Whisstock_2006"/><ref>{{cite journal | vauthors = Whisstock JC, Skinner R, Carrell RW, Lesk AM | title = Conformational changes in serpins: I. The native and cleaved conformations of alpha(1)-antitrypsin | journal = Journal of Molecular Biology | volume = 296 | issue = 2 | pages = 685–699 | date = February 2000 | pmid = 10669617 | doi = 10.1006/jmbi.1999.3520 }}</ref>

[[Serine protease|Serine]] and [[cysteine protease]]s catalyse peptide bond cleavage by a two-step process. Initially, the [[catalytic residue]] of the active site [[Catalytic triad|triad]] performs a [[nucleophile|nucleophilic]] attack on the peptide bond of the substrate. This releases the new [[N-terminus]] and forms a covalent [[ester]]-bond between the enzyme and the substrate.<ref name="Gettins_2002"/> This covalent complex between enzyme and substrate is called an [[acyl-enzyme intermediate]]. For standard [[Substrate (chemistry)|substrates]], the ester bond is [[Hydrolysis|hydrolysed]] and the new [[C-terminus]] is released to complete catalysis. However, when a serpin is cleaved by a protease, it rapidly undergoes the S to R transition before the acyl-enzyme intermediate is hydrolysed.<ref name="Gettins_2002"/> The efficiency of inhibition depends on fact that the relative [[Enzyme kinetics|kinetic rate]] of the conformational change is several orders of magnitude faster than hydrolysis by the protease.

Since the RCL is still covalently attached to the protease via the ester bond, the S to R transition pulls protease from the top to the bottom of the serpin and distorts the catalytic triad. The distorted protease can only hydrolyse the acyl enzyme intermediate extremely slowly and so the protease remains covalently attached for days to weeks.<ref name="Huntington_2000" /> Serpins are classed as [[Irreversible inhibition|irreversible inhibitors]] and as [[suicide inhibitor]]s since each serpin protein permanently inactivates a single protease, and can only function once.<ref name="Gettins_2002" />

{{multiple image
 | align    = center
 | direction = 
| width = 
| image1   = Serpin mechanism (S to R).png
 | width1   = 400
 | alt1     = Conformational change diagram
 | caption1 = The inhibitory mechanism of serpins involves a large [[conformational change]] (S to R transition). The serpin (white) first binds a protease (grey) with the exposed reactive centre loop (blue). When this loop is cleaved by the protease, it rapidly inserts into the A-sheet (light blue), deforming and inhibiting the protease. ({{PDB|1K9O|1EZX}})
 | image2   = Serpin mechanism.png
 | width2   = 484
 | alt2     = Serpin mechanism diagram
| caption2 = [[Serine protease|Serine]] and [[cysteine protease]]s operate by a two-step catalytic mechanism. First, the [[Substrate (chemistry)|substrate]] (blue) is [[Nucleophilic attack|attacked]] by the cysteine or serine of the [[catalytic triad]] (red) to form an [[acyl-enzyme intermediate]]. For typical substrates, the intermediate is resolved by [[hydrolysis]] by water. However, when the reactive centre loop (RCL) of a serpin is attacked, the [[conformational change]] (blue arrow) pulls the catalytic triad out of position, preventing it from completing catalysis. (Based on {{PDB|1K9O|1EZX}})
 }}

===Allosteric activation===
[[File:Serpin activation by heparin (unannotated).png|thumb|600px|Some serpins are activated by cofactors. The serpin [[antithrombin]] has an RCL (blue) where the P1 arginine (blue sticks) points inwards, preventing protease binding. Binding of [[heparin]] (green sticks) causes the P1 arginine residue to flip to an exposed position. The target protease (grey) then binds to both the exposed P1 arginine as well as the heparin. The serpin then activates and heparin is released. ({{PDB|1TB6|2ANT|1TB6|1EZX}})|alt= Diagram of serpin activation by heparin]]
The [[conformational change|conformational mobility]] of serpins provides a key advantage over static lock-and-key protease inhibitors.<ref name="Huntington_2006"/> In particular, the function of inhibitory serpins can be [[Allosteric regulation#Allosteric modulation|regulated]] by [[allosteric]] interactions with specific [[cofactor (biochemistry)|cofactor]]s. The [[X-ray crystallography|X-ray crystal structures]] of [[antithrombin]], [[heparin cofactor II]], [[myeloid and erythroid nuclear termination stage-specific protein|MENT]] and murine [[alpha 1-antichymotrypsin|antichymotrypsin]] reveal that these serpins adopt a conformation wherein the first two amino acids of the RCL are inserted into the top of the A [[β-sheet]]. The partially inserted conformation is important because co-factors are able to conformationally switch certain partially inserted serpins into a fully expelled form.<ref>{{cite journal | vauthors = Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW | title = The anticoagulant activation of antithrombin by heparin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 26 | pages = 14683–14688 | date = December 1997 | pmid = 9405673 | pmc = 25092 | doi = 10.1073/pnas.94.26.14683 | doi-access = free | bibcode = 1997PNAS...9414683J }}</ref><ref>{{cite journal | vauthors = Whisstock JC, Pike RN, Jin L, Skinner R, Pei XY, Carrell RW, Lesk AM | title = Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin | journal = Journal of Molecular Biology | volume = 301 | issue = 5 | pages = 1287–1305 | date = September 2000 | pmid = 10966821 | doi = 10.1006/jmbi.2000.3982 }}</ref> This conformational rearrangement makes the serpin a more effective inhibitor.

The archetypal example of this situation is antithrombin, which circulates in plasma in a partially inserted relatively inactive state. The primary specificity determining residue (the P1 arginine) points toward the body of the serpin and is unavailable to the protease. Upon binding a high-affinity pentasaccharide sequence within long-chain [[heparin]], antithrombin undergoes a conformational change, RCL expulsion, and exposure of the P1 arginine. The heparin pentasaccharide-bound form of antithrombin is, thus, a more effective inhibitor of [[thrombin]] and [[factor Xa]].<ref>{{cite journal | vauthors = Li W, Johnson DJ, Esmon CT, Huntington JA | title = Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin | journal = Nature Structural & Molecular Biology | volume = 11 | issue = 9 | pages = 857–862 | date = September 2004 | pmid = 15311269 | doi = 10.1038/nsmb811 | s2cid = 28790576 }}</ref><ref>{{cite journal | vauthors = Johnson DJ, Li W, Adams TE, Huntington JA | title = Antithrombin-S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation | journal = The EMBO Journal | volume = 25 | issue = 9 | pages = 2029–2037 | date = May 2006 | pmid = 16619025 | pmc = 1456925 | doi = 10.1038/sj.emboj.7601089 }}</ref> Furthermore, both of these coagulation proteases also contain binding sites (called [[Exosite (biology)|exosite]]s) for heparin. Heparin, therefore, also acts as a template for binding of both protease and serpin, further dramatically accelerating the interaction between the two parties. After the initial interaction, the final serpin complex is formed and the heparin moiety is released. This interaction is physiologically important. For example, after injury to the blood vessel wall, heparin is exposed, and antithrombin is activated to control the clotting response. Understanding of the molecular basis of this interaction enabled the development of [[Fondaparinux]], a synthetic form of Heparin pentasaccharide used as an [[anticoagulant|anti-clotting drug]].<ref>{{cite journal | vauthors = Walenga JM, Jeske WP, Samama MM, Frapaise FX, Bick RL, Fareed J | title = Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent | journal = Expert Opinion on Investigational Drugs | volume = 11 | issue = 3 | pages = 397–407 | date = March 2002 | pmid = 11866668 | doi = 10.1517/13543784.11.3.397 | s2cid = 24796086 }}</ref><ref>{{cite journal | vauthors = Petitou M, van Boeckel CA | title = A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? | journal = Angewandte Chemie | volume = 43 | issue = 24 | pages = 3118–3133 | date = June 2004 | pmid = 15199558 | doi = 10.1002/anie.200300640 | bibcode = 2004ACIE...43.3118P }}</ref>

=== Latent conformation ===
[[File:Serpin latent state (unannotated).png|thumb|450x450px|Some serpins can spontaneously convert to an inactive latent state. The serpin [[PAI-1]] remains in the active conformation when bound to [[vitronectin]] (green). However, in the absence of vitronectin, PAI-1 can change to the inactive latent state. The uncleaved RCL (blue; disordered regions as dashed lines) inserts into the A-sheet, pulling a β-strand off the C-sheet (yellow). ({{PDB|1OC0|1DVM|1LJ5}})| alt=Serpin latent state diagram]]

Certain serpins spontaneously undergo the S to R transition without having been cleaved by a protease, to form a conformation termed the latent state. Latent serpins are unable to interact with proteases and so are no longer protease inhibitors. The conformational change to latency is not exactly the same as the S to R transition of a cleaved serpin. Since the RCL is still intact, the first strand of the C-sheet has to peel off to allow full RCL insertion.<ref name="Lindahl_1989">{{cite journal | vauthors = Lindahl TL, Sigurdardottir O, Wiman B | title = Stability of plasminogen activator inhibitor 1 (PAI-1) | journal = Thrombosis and Haemostasis | volume = 62 | issue = 2 | pages = 748–751 | date = September 1989 | pmid = 2479113 | doi = 10.1055/s-0038-1646895 | s2cid = 19433778 }}</ref>

Regulation of the latency transition can act as a control mechanism in some serpins, such as [[PAI-1]]. Although PAI-1 is produced in the inhibitory S conformation, it "auto-inactivates" by changing to the latent state unless it is bound to the cofactor [[vitronectin]].<ref name="Lindahl_1989"/> Similarly, antithrombin can also spontaneously convert to the latent state, as an additional modulation mechanism to its allosteric activation by heparin.<ref>{{cite journal | vauthors = Mushunje A, Evans G, Brennan SO, Carrell RW, Zhou A | title = Latent antithrombin and its detection, formation and turnover in the circulation | journal = Journal of Thrombosis and Haemostasis | volume = 2 | issue = 12 | pages = 2170–2177 | date = December 2004 | pmid = 15613023 | doi = 10.1111/j.1538-7836.2004.01047.x | s2cid = 43029244 | doi-access = free }}</ref> Finally, the N-terminus of {{proper name|tengpin}}, a serpin from ''[[Thermoanaerobacter|Thermoanaerobacter tengcongensis]]'', is required to lock the molecule in the native inhibitory state. Disruption of interactions made by the N-terminal region results in spontaneous conformational change of this serpin to the latent conformation.<ref>{{cite journal | vauthors = Zhang Q, Buckle AM, Law RH, Pearce MC, Cabrita LD, Lloyd GJ, Irving JA, Smith AI, Ruzyla K, Rossjohn J, Bottomley SP, Whisstock JC | title = The N terminus of the serpin, tengpin, functions to trap the metastable native state | journal = EMBO Reports | volume = 8 | issue = 7 | pages = 658–663 | date = July 2007 | pmid = 17557112 | pmc = 1905895 | doi = 10.1038/sj.embor.7400986 }}</ref><ref name="Zhang_2008">{{cite journal | vauthors = Zhang Q, Law RH, Bottomley SP, Whisstock JC, Buckle AM | title = A structural basis for loop C-sheet polymerization in serpins | journal = Journal of Molecular Biology | volume = 376 | issue = 5 | pages = 1348–1359 | date = March 2008 | pmid = 18234218 | doi = 10.1016/j.jmb.2007.12.050 }}</ref>

=== Conformational change in non-inhibitory functions ===
Certain non-inhibitory serpins also use the serpin conformational change as part of their function. For example, the native (S) form of [[thyroxine-binding globulin]] has high affinity for thyroxine, whereas the cleaved (R) form has low affinity. Similarly, [[transcortin]] has higher affinity for cortisol when in its native (S) state, than its cleaved (R) state. Thus, in these serpins, RCL cleavage and the S to R transition has been commandeered to allow for ligand release, rather than protease inhibition.<ref name="cbg"/><ref name="Zhou_2006">{{cite journal | vauthors = Zhou A, Wei Z, Read RJ, Carrell RW | title = Structural mechanism for the carriage and release of thyroxine in the blood | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 36 | pages = 13321–13326 | date = September 2006 | pmid = 16938877 | pmc = 1557382 | doi = 10.1073/pnas.0604080103 | doi-access = free | bibcode = 2006PNAS..10313321Z }}</ref><ref>{{cite journal | vauthors = Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW | title = Hormone binding globulins undergo serpin conformational change in inflammation | journal = Nature | volume = 336 | issue = 6196 | pages = 257–258 | date = November 1988 | pmid = 3143075 | doi = 10.1038/336257a0 | s2cid = 4326356 | bibcode = 1988Natur.336..257P }}</ref>

In some serpins, the S to R transition can activate [[Cell signaling|cell signalling]] events. In these cases, a serpin that has formed a complex with its target protease, is then recognised by a receptor. The binding event then leads to downstream signalling by the receptor.<ref name="Cao_2006">{{cite journal | vauthors = Cao C, Lawrence DA, Li Y, Von Arnim CA, Herz J, Su EJ, Makarova A, Hyman BT, Strickland DK, Zhang L | title = Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration | journal = The EMBO Journal | volume = 25 | issue = 9 | pages = 1860–1870 | date = May 2006 | pmid = 16601674 | pmc = 1456942 | doi = 10.1038/sj.emboj.7601082 }}</ref> The S to R transition is therefore used to alert cells to the presence of protease activity.<ref name="Cao_2006"/> This differs from the usual mechanism whereby serpins affect signalling simply by inhibiting proteases involved in a signalling cascade.<ref name="Acosta 1146–1158"/><ref name="Hashimoto 945–950"/>

==Degradation==
When a serpin inhibits a target protease, it forms a permanent complex, which needs to be disposed of. For extracellular serpins, the final serpin-enzyme complexes are rapidly cleared from circulation. One mechanism by which this occurs in mammals is via the low-density lipoprotein receptor-related protein ([[LRP1|LRP]]), which binds to inhibitory complexes made by antithrombin, PA1-1, and neuroserpin, causing [[Endocytosis|cellular uptake]].<ref name="Cao_2006" /><ref name="Jensen_2009">{{cite journal | vauthors = Jensen JK, Dolmer K, Gettins PG | title = Specificity of binding of the low density lipoprotein receptor-related protein to different conformational states of the clade E serpins plasminogen activator inhibitor-1 and proteinase nexin-1 | journal = The Journal of Biological Chemistry | volume = 284 | issue = 27 | pages = 17989–17997 | date = July 2009 | pmid = 19439404 | pmc = 2709341 | doi = 10.1074/jbc.M109.009530 | doi-access = free }}</ref> Similarly, the ''[[Drosophila]]'' necrotic serpin is degraded in the [[lysosome]] after being trafficked into the cell by the Lipophorin Receptor-1 (homologous to the mammalian [[LDL receptor]] family).<ref name="Soukup_2009">{{cite journal | vauthors = Soukup SF, Culi J, Gubb D | title = Uptake of the necrotic serpin in Drosophila melanogaster via the lipophorin receptor-1 | journal = PLOS Genetics | volume = 5 | issue = 6 | article-number = e1000532 | date = June 2009 | pmid = 19557185 | pmc = 2694266 | doi = 10.1371/journal.pgen.1000532 | veditors = Rulifson E | doi-access = free }}</ref>

==Disease and serpinopathies==
Serpins are involved in a wide array of physiological functions, and so mutations in genes encoding them can cause a range of diseases. Mutations that change the activity, specificity or aggregation properties of serpins all affect how they function. The majority of serpin-related diseases are the result of serpin polymerisation into aggregates, though several other types of disease-linked mutations also occur.<ref name="Whisstock_2006" /><ref>{{cite journal | vauthors = Kaiserman D, Whisstock JC, Bird PI | title = Mechanisms of serpin dysfunction in disease | journal = Expert Reviews in Molecular Medicine | volume = 8 | issue = 31 | pages = 1–19 | date = December 2006 | pmid = 17156576 | doi = 10.1017/S1462399406000184 | s2cid = 20760165 }}</ref> The disorder [[alpha-1 antitrypsin deficiency]] is one of the most common [[hereditary disease]]s.<ref name="Janciauskiene_2011"/><ref name="de_Serres_2002">{{cite journal | vauthors = de Serres FJ | title = Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys | journal = Chest | volume = 122 | issue = 5 | pages = 1818–1829 | date = November 2002 | pmid = 12426287 | doi = 10.1378/chest.122.5.1818 }}</ref>

=== Inactivity or absence ===
[[File:Serpin delta conformation.png|thumb|The inactive δ-conformation of the disease-linked antichymotrypsin mutant (L55P). Four residues of the RCL (blue; disordered region as dashed line) are inserted into the top of the A-sheet. Part of the F α-helix (yellow) has unwound and fills the bottom half of the A-sheet. ({{PDB|1QMN}})|alt=Serpin delta-conformation diagram]]
Since the stressed serpin fold is high-energy, mutations can cause them to incorrectly change into their lower-energy conformations (e.g. relaxed or latent) before they have correctly performed their inhibitory role.<ref name="Stein_1995"/>

Mutations that affect the rate or the extent of RCL insertion into the A-sheet can cause the serpin to undergo its S to R conformational change before having engaged a protease. Since a serpin can only make this conformational change once, the resulting misfired serpin is inactive and unable to properly control its target protease.<ref name="Stein_1995"/><ref>{{cite journal | vauthors = Hopkins PC, Carrell RW, Stone SR | title = Effects of mutations in the hinge region of serpins | journal = Biochemistry | volume = 32 | issue = 30 | pages = 7650–7657 | date = August 1993 | pmid = 8347575 | doi = 10.1021/bi00081a008 }}</ref> Similarly, mutations that promote inappropriate transition to the monomeric latent state cause disease by reducing the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants ''wibble'' and ''wobble'',<ref>{{cite journal | vauthors = Beauchamp NJ, Pike RN, Daly M, Butler L, Makris M, Dafforn TR, Zhou A, Fitton HL, Preston FE, Peake IR, Carrell RW | title = Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation | journal = Blood | volume = 92 | issue = 8 | pages = 2696–2706 | date = October 1998 | pmid = 9763552 | doi = 10.1182/blood.V92.8.2696 }}</ref> both promote formation of the [[Antithrombin#Cleaved and latent antithrombin|latent state]].

The structure of the disease-linked mutant of antichymotrypsin (L55P) revealed another, inactive "δ-conformation". In the δ-conformation, four residues of the RCL are inserted into the top of β-sheet A. The bottom half of the sheet is filled as a result of one of the α-helices (the F-helix) partially switching to a β-strand conformation, completing the β-sheet hydrogen bonding.<ref name="Gooptu_2000">{{cite journal | vauthors = Gooptu B, Hazes B, Chang WS, Dafforn TR, Carrell RW, Read RJ, Lomas DA | title = Inactive conformation of the serpin alpha(1)-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 1 | pages = 67–72 | date = January 2000 | pmid = 10618372 | pmc = 26617 | doi = 10.1073/pnas.97.1.67 | doi-access = free | bibcode = 2000PNAS...97...67G }}</ref> It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role, but it is speculated that the δ-conformation may be adopted by Thyroxine-binding globulin during thyroxine release.<ref name="Zhou_2006"/> The non-inhibitory proteins related to serpins can also cause diseases when mutated. For example, mutations in SERPINF1 cause [[osteogenesis imperfecta]] type VI in humans.<ref name="Homan_2011"/>

In the absence of a required serpin, the protease that it normally would regulate is over-active, leading to pathologies.<ref name="Stein_1995"/> Consequently, simple deficiency of a serpin (e.g. a [[null mutation]]) can result in disease.<ref>{{cite journal | vauthors = Fay WP, Parker AC, Condrey LR, Shapiro AD | title = Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene | journal = Blood | volume = 90 | issue = 1 | pages = 204–208 | date = July 1997 | pmid = 9207454 | doi = 10.1182/blood.V90.1.204 | doi-access = free }}</ref> [[Gene knockout]]s, particularly in [[Knockout mouse|mice]], are used experimentally to determine the normal functions of serpins by the effect of their absence.<ref name="Heit_2013"/>

=== Specificity change ===
In some rare cases, a single amino acid change in a serpin's RCL alters its specificity to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (M358R) causes the [[α1-antitrypsin]] serpin to inhibit thrombin, causing a [[bleeding]] disorder.<ref name="Mutation of antitrypsin to antithro"/>

=== Polymerisation and aggregation ===
{{multiple image
 | header    = Serpin polymerisation by domain swapping
 | direction = vertical
 | width     = 280
 | image1    = Domainswappeddimer.png
 | caption1  = A domain-swapped serpin dimer. ({{PDB|2ZNH}})
 | alt1      = Diagram of a domain-swapped serpin dimer
 | image2    = Antitrypsindomswap.png
 | caption2  = A domain-swapped serpin trimer. Each monomer's RCL is inserted into its own structure (shown in red of the green monomer). ({{PDB|3T1P}})
 | alt2      = Diagram of a domain-swapped serpin trimer
}}

The majority of serpin diseases are due to [[protein aggregation]] and are termed "serpinopathies".<ref name="Carrell_1997" /><ref name="Gooptu_2000"/> Serpins are vulnerable to disease-causing mutations that promote formation of misfolded polymers due to their inherently unstable structures.<ref name="Gooptu_2000"/> Well-characterised serpinopathies include [[alpha 1-antitrypsin deficiency|α1-antitrypsin deficiency]] (alpha-1), which may cause familial [[Pneumatosis#Lungs|emphysema]], and sometimes [[liver cirrhosis]], certain familial forms of [[thrombosis]] related to [[antithrombin deficiency]], types&nbsp;1 and 2 [[angioedema|hereditary angioedema]] (HAE) related to deficiency of [[C1-inhibitor]], and [[familial encephalopathy with neuroserpin inclusion bodies]] (FENIB; a rare type of [[dementia]] caused by neuroserpin polymerisation).<ref name="Janciauskiene_2011"/><ref name="Carrell_1997"/><ref name="lomas_1992">{{cite journal | vauthors = Lomas DA, Evans DL, Finch JT, Carrell RW | title = The mechanism of Z alpha 1-antitrypsin accumulation in the liver | journal = Nature | volume = 357 | issue = 6379 | pages = 605–607 | date = June 1992 | pmid = 1608473 | doi = 10.1038/357605a0 | s2cid = 4359543 | bibcode = 1992Natur.357..605L }}</ref>

Each monomer of the serpin aggregate exists in the inactive, relaxed conformation (with the RCL inserted into the A-sheet). The polymers are therefore hyperstable to temperature and unable to inhibit proteases. Serpinopathies therefore cause pathologies similarly to other [[proteopathy|proteopathies]] (e.g. [[prion]] diseases) via two main mechanisms.<ref name="Janciauskiene_2011"/><ref name="Carrell_1997">{{cite journal | vauthors = Carrell RW, Lomas DA | title = Conformational disease | journal = Lancet | volume = 350 | issue = 9071 | pages = 134–138 | date = July 1997 | pmid = 9228977 | doi = 10.1016/S0140-6736(97)02073-4 | s2cid = 39124185 }}</ref> First, the lack of active serpin results in uncontrolled protease activity and tissue destruction. Second, the hyperstable polymers themselves clog up the [[endoplasmic reticulum]] of cells that synthesize serpins, eventually resulting in cell death and tissue damage. In the case of antitrypsin deficiency, antitrypsin polymers cause the death of [[Hepatocyte|liver cells]], sometimes resulting in liver damage and [[cirrhosis]]. Within the cell, serpin polymers are slowly removed via degradation in the endoplasmic reticulum.<ref name="Kroeger_2009">{{cite journal | vauthors = Kroeger H, Miranda E, MacLeod I, Pérez J, Crowther DC, Marciniak SJ, Lomas DA | title = Endoplasmic reticulum-associated degradation (ERAD) and autophagy cooperate to degrade polymerogenic mutant serpins | journal = The Journal of Biological Chemistry | volume = 284 | issue = 34 | pages = 22793–22802 | date = August 2009 | pmid = 19549782 | pmc = 2755687 | doi = 10.1074/jbc.M109.027102 | doi-access = free }}</ref> However, the details of how serpin polymers cause cell death remains to be fully understood.<ref name="Janciauskiene_2011"/>

Physiological serpin polymers are thought to form via [[Protein domain|domain swapping]] events, where a segment of one serpin protein inserts into another.<ref name="Yamasaki_2008">{{cite journal | vauthors = Yamasaki M, Li W, Johnson DJ, Huntington JA | title = Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization | journal = Nature | volume = 455 | issue = 7217 | pages = 1255–1258 | date = October 2008 | pmid = 18923394 | doi = 10.1038/nature07394 | s2cid = 205215121 | bibcode = 2008Natur.455.1255Y }}</ref> Domain-swaps occur when mutations or environmental factors interfere with the final stages of serpin folding to the native state, causing high-energy intermediates to misfold.<ref name="Bottomley_2011">{{cite journal | vauthors = Bottomley SP | title = The structural diversity in α1-antitrypsin misfolding | journal = EMBO Reports | volume = 12 | issue = 10 | pages = 983–984 | date = September 2011 | pmid = 21921939 | pmc = 3185355 | doi = 10.1038/embor.2011.187 }}</ref> Both [[protein dimer|dimer]] and [[protein trimer|trimer]] domain-swap structures have been solved. In the dimer (of antithrombin), the RCL and part of the A-sheet incorporates into the A-sheet of another serpin molecule.<ref name="Yamasaki_2008"/> The domain-swapped trimer (of antitrypsin) forms via the exchange of an entirely different region of the structure, the B-sheet (with each molecule's RCL inserted into its own A-sheet).<ref name="Yamasaki_2011">{{cite journal | vauthors = Yamasaki M, Sendall TJ, Pearce MC, Whisstock JC, Huntington JA | title = Molecular basis of α1-antitrypsin deficiency revealed by the structure of a domain-swapped trimer | journal = EMBO Reports | volume = 12 | issue = 10 | pages = 1011–1017 | date = September 2011 | pmid = 21909074 | pmc = 3185345 | doi = 10.1038/embor.2011.171 }}</ref> It has also been proposed that serpins may form domain-swaps by inserting the RCL of one protein into the A-sheet of another (A-sheet polymerisation).<ref name="lomas_1992"/><ref>{{cite journal | vauthors = Chang WS, Whisstock J, Hopkins PC, Lesk AM, Carrell RW, Wardell MR | title = Importance of the release of strand 1C to the polymerization mechanism of inhibitory serpins | journal = Protein Science | volume = 6 | issue = 1 | pages = 89–98 | date = January 1997 | pmid = 9007980 | pmc = 2143506 | doi = 10.1002/pro.5560060110 }}</ref> These domain-swapped dimer and trimer structures are thought to be the building blocks of the disease-causing polymer aggregates, but the exact mechanism is still unclear.<ref name="Yamasaki_2008"/><ref name="Bottomley_2011"/><ref name="Yamasaki_2011"/><ref name="Miranda_2010">{{cite journal | vauthors = Miranda E, Pérez J, Ekeowa UI, Hadzic N, Kalsheker N, Gooptu B, Portmann B, Belorgey D, Hill M, Chambers S, Teckman J, Alexander GJ, Marciniak SJ, Lomas DA | title = A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency | journal = Hepatology | volume = 52 | issue = 3 | pages = 1078–1088 | date = September 2010 | pmid = 20583215 | doi = 10.1002/hep.23760 | s2cid = 8188156 }}</ref>

====Therapeutic strategies====
Several therapeutic approaches are in use or under investigation to treat the most common serpinopathy: antitrypsin deficiency.<ref name="Janciauskiene_2011"/> Antitrypsin augmentation therapy is approved for severe antitrypsin deficiency-related emphysema.<ref name="Sandhaus_2004">{{cite journal | vauthors = Sandhaus RA | title = alpha1-Antitrypsin deficiency . 6: new and emerging treatments for alpha1-antitrypsin deficiency | journal = Thorax | volume = 59 | issue = 10 | pages = 904–909 | date = October 2004 | pmid = 15454659 | pmc = 1746849 | doi = 10.1136/thx.2003.006551 }}</ref> In this therapy, antitrypsin is purified from the plasma of blood donors and administered intravenously (first marketed as [[Prolastin]]).<ref name="Janciauskiene_2011"/><ref>{{cite journal | vauthors = Lewis EC | title = Expanding the clinical indications for α(1)-antitrypsin therapy | journal = Molecular Medicine | volume = 18 | issue = 6 | pages = 957–970 | date = September 2012 | pmid = 22634722 | pmc = 3459478 | doi = 10.2119/molmed.2011.00196 }}</ref> To treat severe antitrypsin deficiency-related disease, lung and liver [[Organ transplantation|transplantation]] has proven effective.<ref name="Janciauskiene_2011"/><ref name="Fregonese_2008">{{cite journal | vauthors = Fregonese L, Stolk J | title = Hereditary alpha-1-antitrypsin deficiency and its clinical consequences | journal = Orphanet Journal of Rare Diseases | volume = 3 | article-number = 16 | date = June 2008 | pmid = 18565211 | pmc = 2441617 | doi = 10.1186/1750-1172-3-16 | doi-access = free }}</ref> In animal models, gene targeting in [[induced pluripotent stem cell]]s has been successfully used to correct an antitrypsin polymerisation defect and to restore the ability of the mammalian liver to secrete active antitrypsin.<ref name="Yusa_2011">{{cite journal | vauthors = Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordóñez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ, Fusaki N, Hasegawa M, Holmes MC, Di Santo JP, Lomas DA, Bradley A, Vallier L | title = Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells | journal = Nature | volume = 478 | issue = 7369 | pages = 391–394 | date = October 2011 | pmid = 21993621 | pmc = 3198846 | doi = 10.1038/nature10424 | bibcode = 2011Natur.478..391Y }}</ref> Small molecules have also been developed that block antitrypsin polymerisation ''in vitro''.<ref name="Mallya_2007">{{cite journal | vauthors = Mallya M, Phillips RL, Saldanha SA, Gooptu B, Brown SC, Termine DJ, Shirvani AM, Wu Y, Sifers RN, Abagyan R, Lomas DA | title = Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates | journal = Journal of Medicinal Chemistry | volume = 50 | issue = 22 | pages = 5357–5363 | date = November 2007 | pmid = 17918823 | pmc = 2631427 | doi = 10.1021/jm070687z }}</ref><ref name="Gosai_2010">{{cite journal | vauthors = Gosai SJ, Kwak JH, Luke CJ, Long OS, King DE, Kovatch KJ, Johnston PA, Shun TY, Lazo JS, Perlmutter DH, Silverman GA, Pak SC | title = Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z | journal = PLOS ONE | volume = 5 | issue = 11 | article-number = e15460 | date = November 2010 | pmid = 21103396 | pmc = 2980495 | doi = 10.1371/journal.pone.0015460 | doi-access = free | bibcode = 2010PLoSO...515460G }}</ref>

==Evolution==
Serpins are the most widely distributed and largest superfamily of protease inhibitors.<ref name="Silverman_2001" /><ref name="Rawlings_2004"/> They were initially believed to be restricted to [[eukaryote]] organisms, but have since been found in [[bacteria]], [[archaea]] and some [[viruses]].<ref name="Irving_2000"/><ref name="Irving_2002">{{cite journal | vauthors = Irving JA, Steenbakkers PJ, Lesk AM, Op den Camp HJ, Pike RN, Whisstock JC | title = Serpins in prokaryotes | journal = Molecular Biology and Evolution | volume = 19 | issue = 11 | pages = 1881–1890 | date = November 2002 | pmid = 12411597 | doi = 10.1093/oxfordjournals.molbev.a004012 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cabrita LD, Irving JA, Pearce MC, Whisstock JC, Bottomley SP | title = Aeropin from the extremophile Pyrobaculum aerophilum bypasses the serpin misfolding trap | journal = The Journal of Biological Chemistry | volume = 282 | issue = 37 | pages = 26802–26809 | date = September 2007 | pmid = 17635906 | doi = 10.1074/jbc.M705020200 | doi-access = free }}</ref> It remains unclear whether prokaryote genes are the descendants of an ancestral prokaryotic serpin or the product of [[horizontal gene transfer]] from eukaryotes. Most intracellular serpins belong to a single [[phylogenetic]] clade, whether they come from plants or animals, indicating that the intracellular and extracellular serpins may have diverged before the plants and animals.<ref>{{cite journal | vauthors = Fluhr R, Lampl N, Roberts TH | title = Serpin protease inhibitors in plant biology | journal = Physiologia Plantarum | volume = 145 | issue = 1 | pages = 95–102 | date = May 2012 | pmid = 22085334 | doi = 10.1111/j.1399-3054.2011.01540.x | bibcode = 2012PPlan.145...95F }}</ref> Exceptions include the intracellular heat shock serpin HSP47, which is a chaperone essential for proper folding of [[collagen]], and cycles between the [[Golgi apparatus|cis-Golgi]] and the [[endoplasmic reticulum]].<ref name="Mala_2010" />

Protease-inhibition is thought to be the ancestral function, with non-inhibitory members the results of evolutionary [[neofunctionalisation]] of the structure. The S to R conformational change has also been adapted by some binding serpins to regulate affinity for their targets.<ref name="Zhou_2006"/>

==Distribution==

===Animal===

====Human====
The human genome encodes 16&nbsp;serpin clades, termed {{proper name|serpinA}} through {{proper name|serpinP}}, including 29&nbsp;inhibitory and 7&nbsp;non-inhibitory serpin proteins.<ref name="Law_2006" /><ref name="Heit_2013" /> The human serpin naming system is based upon a [[phylogenetic]] analysis of approximately 500&nbsp;serpins from 2001, with proteins named {{proper name|serpinXY}}, where X is the clade of the protein and Y the number of the protein within that clade.<ref name="Silverman_2001" /><ref name="Irving_2000">{{cite journal | vauthors = Irving JA, Pike RN, Lesk AM, Whisstock JC | title = Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function | journal = Genome Research | volume = 10 | issue = 12 | pages = 1845–1864 | date = December 2000 | pmid = 11116082 | doi = 10.1101/gr.GR-1478R | doi-access = free }}</ref><ref name="Heit_2013" /> The functions of human serpins have been determined by a combination of [[Biochemistry|biochemical]] studies, human [[genetic disorder]]s, and [[Knockout mouse|knockout mouse models]].<ref name="Heit_2013" />

<!--------------------------------------------
 When adding to the 'Human disease' column of
 this table, please cite secondary / tertiary
 medical sources. (See WP:MEDRS for details)
--------------------------------------------->
{| class="wikitable sortable mw-collapsible mw-collapsed" style="width:100%;"
|+ style="border:#aaa 1px solid; background:#eaeaea; padding:0.1em;" | Table of human serpins
|-
! Gene name
! Common name
! Localisation
! class="unsortable" | Function / Activity<ref name="Law_2006">{{cite journal | vauthors = Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC | title = An overview of the serpin superfamily | journal = Genome Biology | volume = 7 | issue = 5 | page = 216 | year = 2006 | pmid = 16737556 | pmc = 1779521 | doi = 10.1186/gb-2006-7-5-216 | doi-access = free }}</ref><ref name="Heit_2013">{{cite journal | vauthors = Heit C, Jackson BC, McAndrews M, Wright MW, Thompson DC, Silverman GA, Nebert DW, Vasiliou V | title = Update of the human and mouse SERPIN gene superfamily | journal = Human Genomics | volume = 7 | article-number = 22 | date = October 2013 | issue = 1 | pmid = 24172014 | pmc = 3880077 | doi = 10.1186/1479-7364-7-22 | doi-access = free }}</ref>
! class="unsortable" | Effect of deficiency<ref name="Law_2006"/><ref name="Heit_2013"/>
! class="unsortable" | Human disease
! Chromosomal location
! scope="col" style="width: 70px;" | Protein structure
|-
| [[SERPINA1]]
| [[Alpha-1 antitrypsin|α1-antitrypsin]]
|Extracellular
|Inhibitor of human neutrophil elastase.<ref name="Stoller_2005">{{cite journal | vauthors = Stoller JK, Aboussouan LS | title = Alpha1-antitrypsin deficiency | journal = Lancet | volume = 365 | issue = 9478 | pages = 2225–2236 | year = 2005 | pmid = 15978931 | doi = 10.1016/S0140-6736(05)66781-5 | s2cid = 54415934 }}</ref> The C-terminal fragment of cleaved SERPINA1 may inhibit HIV-1 infection.<ref>{{cite journal | vauthors = Münch J, Ständker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, Pöhlmann S, Chaipan C, Biet T, Peters T, Meyer B, Wilhelm D, Lu H, Jing W, Jiang S, Forssmann WG, Kirchhoff F | title = Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide | journal = Cell | volume = 129 | issue = 2 | pages = 263–275 | date = April 2007 | pmid = 17448989 | doi = 10.1016/j.cell.2007.02.042 | doi-access = free }}</ref>
|
|[[Alpha 1-antitrypsin deficiency|Deficiency]] results in emphysema, polymerisation results in cirrhosis (serpinopathy).<ref name="Janciauskiene_2011"/><ref>{{cite journal | vauthors = Gooptu B, Dickens JA, Lomas DA | title = The molecular and cellular pathology of α₁-antitrypsin deficiency | journal = Trends in Molecular Medicine | volume = 20 | issue = 2 | pages = 116–127 | date = February 2014 | pmid = 24374162 | doi = 10.1016/j.molmed.2013.10.007 }}</ref>
| 14q32.1
|{{PDB2|1QLP}}, {{PDB2|7API}}, {{PDB2|1D5S}}
|-
| [[SERPINA2]]
| [[Antitrypsin-related protein]]
|Extracellular
|Possible pseudogene.<ref>{{cite journal | vauthors = Seixas S, Suriano G, Carvalho F, Seruca R, Rocha J, Di Rienzo A | title = Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2 | journal = Molecular Biology and Evolution | volume = 24 | issue = 2 | pages = 587–598 | date = February 2007 | pmid = 17135331 | doi = 10.1093/molbev/msl187 | doi-access = free }}</ref>
|
|
| 14q32.1
|
|-
| [[SERPINA3]]
| [[Alpha 1-antichymotrypsin|α1-antichymotrypsin]]
|Extracellular
|Inhibitor of cathepsin G.<ref name="Kalsheker_1996">{{cite journal | vauthors = Kalsheker NA | title = Alpha 1-antichymotrypsin | journal = The International Journal of Biochemistry & Cell Biology | volume = 28 | issue = 9 | pages = 961–964 | date = September 1996 | pmid = 8930118 | doi = 10.1016/1357-2725(96)00032-5 | s2cid = 11230631 }}</ref> Additional roles in chromatin condensation in hepatic cells.<ref name="Santamaria_2013">{{cite journal | vauthors = Santamaria M, Pardo-Saganta A, Alvarez-Asiain L, Di Scala M, Qian C, Prieto J, Avila MA | title = Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells | journal = Gastroenterology | volume = 144 | issue = 4 | pages = 818–828.e4 | date = April 2013 | pmid = 23295442 | doi = 10.1053/j.gastro.2012.12.029 | doi-access = free }}</ref>
|
|Mis-regulation results in [[Alzheimer's disease]] (serpinopathy).<ref>{{cite journal | vauthors = Zhang S, Janciauskiene S | title = Multi-functional capability of proteins: alpha1-antichymotrypsin and the correlation with Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 4 | issue = 2 | pages = 115–122 | date = April 2002 | pmid = 12214135 | doi = 10.3233/JAD-2002-4206 }}</ref> <!--can only find primary sources on [[emphysema]]-->
| 14q32.1
|{{PDB2|1YXA}}, {{PDB2|2ACH}}
|-
| [[SERPINA4]]
| [[Kallistatin]]
|Extracellular
|Inhibitor of kallikrein, regulator of vascular function.<ref name="Chao_1997">{{cite journal | vauthors = Chao J, Stallone JN, Liang YM, Chen LM, Wang DZ, Chao L | title = Kallistatin is a potent new vasodilator | journal = The Journal of Clinical Investigation | volume = 100 | issue = 1 | pages = 11–17 | date = July 1997 | pmid = 9202051 | pmc = 508159 | doi = 10.1172/JCI119502 }}</ref><ref>{{cite journal | vauthors = Miao RQ, Agata J, Chao L, Chao J | title = Kallistatin is a new inhibitor of angiogenesis and tumor growth | journal = Blood | volume = 100 | issue = 9 | pages = 3245–3252 | date = November 2002 | pmid = 12384424 | doi = 10.1182/blood-2002-01-0185 | doi-access = free }}</ref>
|Depletion in hypertensive rats exacerbates renal and cardiovascular injury.<ref name="Liu_2012">{{cite journal | vauthors = Liu Y, Bledsoe G, Hagiwara M, Shen B, Chao L, Chao J | title = Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling | journal = American Journal of Physiology. Renal Physiology | volume = 303 | issue = 8 | pages = F1230–F1238 | date = October 2012 | pmid = 22811485 | pmc = 3469672 | doi = 10.1152/ajprenal.00257.2012 }}</ref>
|
| 14q32.1
|
|-
| [[SERPINA5]]
| [[Protein C inhibitor]]
|Extracellular
|  Inhibitor of active [[protein C]].<ref name="Geiger_2007">{{cite journal | vauthors = Geiger M | title = Protein C inhibitor, a serpin with functions in- and outside vascular biology | journal = Thrombosis and Haemostasis | volume = 97 | issue = 3 | pages = 343–347 | date = March 2007 | pmid = 17334499 | doi = 10.1160/th06-09-0488 | s2cid = 4828322 }}</ref> Intracellular role in preventing phagocytosis of bacteria.<ref name="Baumgärtner_2007">{{cite journal | vauthors = Baumgärtner P, Geiger M, Zieseniss S, Malleier J, Huntington JA, Hochrainer K, Bielek E, Stoeckelhuber M, Lauber K, Scherfeld D, Schwille P, Wäldele K, Beyer K, Engelmann B | title = Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor | journal = The Journal of Cell Biology | volume = 179 | issue = 4 | pages = 793–804 | date = November 2007 | pmid = 18025309 | pmc = 2080921 | doi = 10.1083/jcb.200707165 }}</ref>
|Knockout in male mice causes infertility.<ref>{{cite journal | vauthors = Uhrin P, Dewerchin M, Hilpert M, Chrenek P, Schöfer C, Zechmeister-Machhart M, Krönke G, Vales A, Carmeliet P, Binder BR, Geiger M | title = Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility | journal = The Journal of Clinical Investigation | volume = 106 | issue = 12 | pages = 1531–1539 | date = December 2000 | pmid = 11120760 | pmc = 381472 | doi = 10.1172/JCI10768 }}</ref> Accumulation occurs in chronic active plaques in [[multiple sclerosis]].<ref name="Han_2008">{{cite journal | vauthors = Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L | title = Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets | journal = Nature | volume = 451 | issue = 7182 | pages = 1076–1081 | date = February 2008 | pmid = 18278032 | doi = 10.1038/nature06559 | s2cid = 4421395 | bibcode = 2008Natur.451.1076H }}</ref>
|
| 14q32.1
|{{PDB2|2OL2}}, {{PDB2|3B9F}}
|-
| [[SERPINA6]]
| [[Transcortin]]
|Extracellular
| Non-inhibitory. Cortisol binding.<ref name="cbg"/>
|
|Deficiency associated with chronic fatigue.<ref>{{cite journal | vauthors = Torpy DJ, Ho JT | title = Corticosteroid-binding globulin gene polymorphisms: clinical implications and links to idiopathic chronic fatigue disorders | journal = Clinical Endocrinology | volume = 67 | issue = 2 | pages = 161–167 | date = August 2007 | pmid = 17547679 | doi = 10.1111/j.1365-2265.2007.02890.x | s2cid = 43352358 | doi-access = free }}</ref>
| 14q32.1
|{{PDB2|2V6D}}, {{PDB2|2VDX}}, {{PDB2|2VDY}}
|-
| [[SERPINA7]]
| [[Thyroxine-binding globulin]]
|Extracellular
|Non-inhibitory. Thyroxine binding.<ref name="Zhou_2006"/>
|
|Deficiency causes hypothyroidism.<ref>{{cite journal | vauthors = Bartalena L, Robbins J | title = Variations in thyroid hormone transport proteins and their clinical implications | journal = Thyroid | volume = 2 | issue = 3 | pages = 237–245 | year = 1992 | pmid = 1422238 | doi = 10.1089/thy.1992.2.237 }}</ref><ref>{{cite journal | vauthors = Persani L | title = Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 9 | pages = 3068–3078 | date = September 2012 | pmid = 22851492 | doi = 10.1210/jc.2012-1616 | doi-access = free }}</ref>
| Xq22.2
|{{PDB2|2CEO}}, {{PDB2|2RIV}}, {{PDB2|2RIW}}
|-
| [[SERPINA8]]
| [[Angiotensinogen]]
|Extracellular
| Non-inhibitory, cleavage by renin results in release of angiotensin I.<ref name="Kumar_2007">{{cite journal | vauthors = Kumar R, Singh VP, Baker KM | title = The intracellular renin-angiotensin system: a new paradigm | journal = Trends in Endocrinology and Metabolism | volume = 18 | issue = 5 | pages = 208–214 | date = July 2007 | pmid = 17509892 | doi = 10.1016/j.tem.2007.05.001 | s2cid = 24041932 }}</ref>
|Knockout in mice causes hypotension.<ref name="Tanimoto_1994">{{cite journal | vauthors = Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K | title = Angiotensinogen-deficient mice with hypotension | journal = The Journal of Biological Chemistry | volume = 269 | issue = 50 | pages = 31334–31337 | date = December 1994 | pmid = 7989296 | doi = 10.1016/S0021-9258(18)31697-1 | doi-access = free }}</ref>
|Variants linked to hypertension.<ref>{{cite journal | vauthors = Jeunemaitre X, Gimenez-Roqueplo AP, Célérier J, Corvol P | title = Angiotensinogen variants and human hypertension | journal = Current Hypertension Reports | volume = 1 | issue = 1 | pages = 31–41 | year = 1999 | pmid = 10981040 | doi = 10.1007/s11906-999-0071-0 | s2cid = 42614761 }}</ref><ref>{{cite journal | vauthors = Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A | title = Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 7 | pages = 1269–1275 | date = July 2003 | pmid = 12805070 | doi = 10.1161/01.ATV.0000079007.40884.5C | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dickson ME, Sigmund CD | title = Genetic basis of hypertension: revisiting angiotensinogen | journal = Hypertension | volume = 48 | issue = 1 | pages = 14–20 | date = July 2006 | pmid = 16754793 | doi = 10.1161/01.HYP.0000227932.13687.60 | doi-access = free }}</ref>
| 1q42-q43
|{{PDB2|2X0B}}, {{PDB2|2WXW}}, {{PDB2|2WXX}}, {{PDB2|2WXY}}, {{PDB2|2WXZ}}, {{PDB2|2WY0}}, {{PDB2|2WY1}}
|-
| [[SERPINA9]]
| [[Centerin]] / GCET1
|Extracellular
| Inhibitory, maintenance of naive B cells.<ref>{{cite journal | vauthors = Frazer JK, Jackson DG, Gaillard JP, Lutter M, Liu YJ, Banchereau J, Capra JD, Pascual V | title = Identification of centerin: a novel human germinal center B cell-restricted serpin | journal = European Journal of Immunology | volume = 30 | issue = 10 | pages = 3039–3048 | date = October 2000 | pmid = 11069088 | doi = 10.1002/1521-4141(200010)30:10<3039::AID-IMMU3039>3.0.CO;2-H | doi-access = free | author-link6 = Jacques Banchereau }}</ref><ref>{{cite journal | vauthors = Paterson MA, Horvath AJ, Pike RN, Coughlin PB | title = Molecular characterization of centerin, a germinal centre cell serpin | journal = The Biochemical Journal | volume = 405 | issue = 3 | pages = 489–494 | date = August 2007 | pmid = 17447896 | pmc = 2267310 | doi = 10.1042/BJ20070174 }}</ref>
|
|Strongly expressed in most B-cell lymphomas.<ref name="Paterson_2008">{{cite journal | vauthors = Paterson MA, Hosking PS, Coughlin PB | title = Expression of the serpin centerin defines a germinal center phenotype in B-cell lymphomas | journal = American Journal of Clinical Pathology | volume = 130 | issue = 1 | pages = 117–126 | date = July 2008 | pmid = 18550480 | doi = 10.1309/9QKE68QU7B825A3U | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ashton-Rickardt PG | title = An emerging role for Serine Protease Inhibitors in T lymphocyte immunity and beyond | journal = Immunology Letters | volume = 152 | issue = 1 | pages = 65–76 | date = April 2013 | pmid = 23624075 | doi = 10.1016/j.imlet.2013.04.004 }}</ref>
| 14q32.1
|
|-
| [[SERPINA10]]
| [[Protein Z-related protease inhibitor]]
|Extracellular
| Binds [[protein Z]] and inactivates [[factor Xa]] and [[factor XI]]a.<ref name="Han_2000">{{cite journal | vauthors = Han X, Fiehler R, Broze GJ | title = Characterization of the protein Z-dependent protease inhibitor | journal = Blood | volume = 96 | issue = 9 | pages = 3049–3055 | date = November 2000 | pmid = 11049983 | doi = 10.1182/blood.V96.9.3049 }}</ref>
|
|
| 14q32.1
|{{PDB2|3F1S}}, {{PDB2|3H5C}}
|-
| [[SERPINA11]]
| –
|Probably extracellular
| Unknown
|
|
| 14q32.13
|
|-
| [[SERPINA12]]
| [[Vaspin]]
|Extracellular
| Inhibitor of Kallikrein-7. Insulin-sensitizing adipocytokine.<ref>{{cite journal | vauthors = Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS | title = Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 30 | pages = 10610–10615 | date = July 2005 | pmid = 16030142 | pmc = 1180799 | doi = 10.1073/pnas.0504703102 | doi-access = free | bibcode = 2005PNAS..10210610H }}</ref>
|
|High plasma levels associated with type II diabetes.<ref>{{cite journal | vauthors = Feng R, Li Y, Wang C, Luo C, Liu L, Chuo F, Li Q, Sun C | title = Higher vaspin levels in subjects with obesity and type 2 diabetes mellitus: a meta-analysis | journal = Diabetes Research and Clinical Practice | volume = 106 | issue = 1 | pages = 88–94 | date = October 2014 | pmid = 25151227 | doi = 10.1016/j.diabres.2014.07.026 }}</ref>
| 14q32.1
|{{PDB2|4IF8}}
|-
| [[SERPINA13]]
| –
|Probably extracellular
| Unknown
|
|
| 14q32
|
|-
| [[SERPINB1]]
| [[SERPINB1|Monocyte neutrophil elastase inhibitor]]
|Intracellular
| Inhibitor of neutrophil elastase.<ref>{{cite journal | vauthors = Remold-O'Donnell E, Chin J, Alberts M | title = Sequence and molecular characterization of human monocyte/neutrophil elastase inhibitor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 12 | pages = 5635–5639 | date = June 1992 | pmid = 1376927 | pmc = 49347 | doi = 10.1073/pnas.89.12.5635 | doi-access = free | bibcode = 1992PNAS...89.5635R }}</ref>
|Knockout in mice causes neutrophil survival defect and immune deficiency.<ref>{{cite journal | vauthors = Benarafa C, Priebe GP, Remold-O'Donnell E | title = The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection | journal = The Journal of Experimental Medicine | volume = 204 | issue = 8 | pages = 1901–1909 | date = August 2007 | pmid = 17664292 | pmc = 2118684 | doi = 10.1084/jem.20070494 }}</ref>
|
| 6p25
|{{PDB2|1HLE}}
|-
| [[SERPINB2]]
| [[Plasminogen activator inhibitor-2]]
|Intracellular/extracellular
| Inhibitor of extracellular uPA. Intracellular function unclear, but may protect against viral infection.<ref name="Antalis_1998">{{cite journal | vauthors = Antalis TM, La Linn M, Donnan K, Mateo L, Gardner J, Dickinson JL, Buttigieg K, Suhrbier A | title = The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming | journal = The Journal of Experimental Medicine | volume = 187 | issue = 11 | pages = 1799–1811 | date = June 1998 | pmid = 9607921 | pmc = 2212304 | doi = 10.1084/jem.187.11.1799 }}</ref>
|Deficiency in mice reduces immune response to nematode infection.<ref name="Zhao_2013">{{cite journal | vauthors = Zhao A, Yang Z, Sun R, Grinchuk V, Netzel-Arnett S, Anglin IE, Driesbaugh KH, Notari L, Bohl JA, Madden KB, Urban JF, Antalis TM, Shea-Donohue T | title = SerpinB2 is critical to Th2 immunity against enteric nematode infection | journal = Journal of Immunology | volume = 190 | issue = 11 | pages = 5779–5787 | date = June 2013 | pmid = 23630350 | pmc = 4068334 | doi = 10.4049/jimmunol.1200293 }}</ref> Knockout in mice causes no obvious phenotype.<ref>{{cite journal | vauthors = Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D | title = The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 2 | pages = 686–691 | date = January 1999 | pmid = 9892694 | pmc = 15197 | doi = 10.1073/pnas.96.2.686 | doi-access = free | bibcode = 1999PNAS...96..686D }}</ref>
|
| 18q21.3
|{{PDB2|1BY7}}
|-
| [[SERPINB3]]
| [[Squamous cell carcinoma antigen-1]] (SCCA-1)
|Intracellular
| Inhibitor of papain-like cysteine proteases<ref name="Schick_1998"/> and cathepsins K, L and S.<ref>{{cite journal | vauthors = Takeda A, Yamamoto T, Nakamura Y, Takahashi T, Hibino T | title = Squamous cell carcinoma antigen is a potent inhibitor of cysteine proteinase cathepsin L | journal = FEBS Letters | volume = 359 | issue = 1 | pages = 78–80 | date = February 1995 | pmid = 7851535 | doi = 10.1016/0014-5793(94)01456-b | s2cid = 35146299 | doi-access = free | bibcode = 1995FEBSL.359...78T }}</ref><ref name="CT">{{cite journal | vauthors = Turato C, Pontisso P | title = SERPINB3 (serpin peptidase inhibitor, clade B (ovalbumin), member 3) | journal = Atlas of Genetics and Cytogenetics in Oncology and Haematology | volume = 19 | issue = 3 | pages = 202–209 | date = March 2015 | pmid = 25984243 | pmc = 4430857 | doi = 10.4267/2042/56413 | doi-broken-date = 12 July 2025 }}</ref>
|Knockout in mice of Serpinb3a (the murine [[homolog]] of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of [[asthma]].<ref name="Sivaprasad_2011" />
|
| 18q21.3
|{{PDB2|2ZV6}}
|-
| [[SERPINB4]]
| [[Squamous cell carcinoma antigen-2]] (SCCA-2)
|Intracellular
| Inhibitor of chymotrypsin-like serine proteases, [[cathepsin G]] and [[chymase]].<ref name="CT" /><ref>{{cite journal | vauthors = Schick C, Kamachi Y, Bartuski AJ, Cataltepe S, Schechter NM, Pemberton PA, Silverman GA | title = Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase | journal = The Journal of Biological Chemistry | volume = 272 | issue = 3 | pages = 1849–1855 | date = January 1997 | pmid = 8999871 | doi = 10.1074/jbc.272.3.1849 | doi-access = free }}</ref>
|Knockout in mice of Serpinb3a (the murine [[homolog]] of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of [[asthma]].<ref name="Sivaprasad_2011">{{cite journal | vauthors = Sivaprasad U, Askew DJ, Ericksen MB, Gibson AM, Stier MT, Brandt EB, Bass SA, Daines MO, Chakir J, Stringer KF, Wert SE, Whitsett JA, Le Cras TD, Wills-Karp M, Silverman GA, Khurana Hershey GK | title = A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma | journal = The Journal of Allergy and Clinical Immunology | volume = 127 | issue = 1 | pages = 254–61, 261.e1–6 | date = January 2011 | pmid = 21126757 | pmc = 3058372 | doi = 10.1016/j.jaci.2010.10.009 }}</ref>
|
| 18q21.3
|
|-
| [[SERPINB5]]
| [[Maspin]]
|Intracellular
| Non-inhibitory, function unclear<ref name="Teoh_2010">{{cite journal | vauthors = Teoh SS, Whisstock JC, Bird PI | title = Maspin (SERPINB5) is an obligate intracellular serpin | journal = The Journal of Biological Chemistry | volume = 285 | issue = 14 | pages = 10862–10869 | date = April 2010 | pmid = 20123984 | pmc = 2856292 | doi = 10.1074/jbc.M109.073171 | doi-access = free }}</ref><ref name="maspin">{{cite journal | vauthors = Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R | title = Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells | journal = Science | volume = 263 | issue = 5146 | pages = 526–529 | date = January 1994 | pmid = 8290962 | doi = 10.1126/science.8290962 | bibcode = 1994Sci...263..526Z }}</ref><ref name="Teoh_2014">{{cite journal | vauthors = Teoh SS, Vieusseux J, Prakash M, Berkowicz S, Luu J, Bird CH, Law RH, Rosado C, Price JT, Whisstock JC, Bird PI | title = Maspin is not required for embryonic development or tumour suppression | journal = Nature Communications | volume = 5 | article-number = 3164 | year = 2014 | pmid = 24445777 | pmc = 3905777 | doi = 10.1038/ncomms4164 | bibcode = 2014NatCo...5.3164T }}</ref> (''see also [[maspin]])''
| Knockout in mice originally reported as lethal,<ref name="Gao_2004">{{cite journal | vauthors = Gao F, Shi HY, Daughty C, Cella N, Zhang M | title = Maspin plays an essential role in early embryonic development | journal = Development | volume = 131 | issue = 7 | pages = 1479–1489 | date = April 2004 | pmid = 14985257 | doi = 10.1242/dev.01048 | doi-access = free }}</ref> but subsequently shown to have no obvious phenotype.<ref name="Teoh_2014"/> Expression may be a prognostic indicator that reflects expression of a neighbouring tumour suppressor gene (the phosphatase [[PHLPP]]1).<ref name="Teoh_2014" />
|
| 18q21.3
|{{PDB2|1WZ9}}
|-
| [[SERPINB6]]
| [[SERPINB6|PI-6]]
|Intracellular
| Inhibitor of cathepsin G.<ref name="Scott_1999">{{cite journal | vauthors = Scott FL, Hirst CE, Sun J, Bird CH, Bottomley SP, Bird PI | title = The intracellular serpin proteinase inhibitor 6 is expressed in monocytes and granulocytes and is a potent inhibitor of the azurophilic granule protease, cathepsin G | journal = Blood | volume = 93 | issue = 6 | pages = 2089–2097 | date = March 1999 | pmid = 10068683 | doi = 10.1182/blood.V93.6.2089.406k10_2089_2097 }}</ref>
|Knockout in mice causes hearing loss<ref>{{cite journal | vauthors = Tan J, Prakash MD, Kaiserman D, Bird PI | title = Absence of SERPINB6A causes sensorineural hearing loss with multiple histopathologies in the mouse inner ear | journal = The American Journal of Pathology | volume = 183 | issue = 1 | pages = 49–59 | date = July 2013 | pmid = 23669344 | doi = 10.1016/j.ajpath.2013.03.009 }}</ref> and mild [[neutropenia]].<ref>{{cite journal | vauthors = Scarff KL, Ung KS, Nandurkar H, Crack PJ, Bird CH, Bird PI | title = Targeted disruption of SPI3/Serpinb6 does not result in developmental or growth defects, leukocyte dysfunction, or susceptibility to stroke | journal = Molecular and Cellular Biology | volume = 24 | issue = 9 | pages = 4075–4082 | date = May 2004 | pmid = 15082799 | pmc = 387772 | doi = 10.1128/MCB.24.9.4075-4082.2004 }}</ref>
|Deficiency associated with [[hearing loss]].<ref>{{cite journal | vauthors = Sirmaci A, Erbek S, Price J, Huang M, Duman D, Cengiz FB, Bademci G, Tokgöz-Yilmaz S, Hişmi B, Ozdağ H, Oztürk B, Kulaksizoğlu S, Yildirim E, Kokotas H, Grigoriadou M, Petersen MB, Shahin H, Kanaan M, King MC, Chen ZY, Blanton SH, Liu XZ, Zuchner S, Akar N, Tekin M | title = A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss | journal = American Journal of Human Genetics | volume = 86 | issue = 5 | pages = 797–804 | date = May 2010 | pmid = 20451170 | pmc = 2869020 | doi = 10.1016/j.ajhg.2010.04.004 }}</ref>
| 6p25
|
|-
| [[SERPINB7]]
| [[Megsin]]
|Intracellular
| Involved in megakaryocyte maturation.<ref>{{cite journal | vauthors = Miyata T, Inagi R, Nangaku M, Imasawa T, Sato M, Izuhara Y, Suzuki D, Yoshino A, Onogi H, Kimura M, Sugiyama S, Kurokawa K | title = Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion | journal = The Journal of Clinical Investigation | volume = 109 | issue = 5 | pages = 585–593 | date = March 2002 | pmid = 11877466 | pmc = 150894 | doi = 10.1172/JCI14336 }}</ref>
|Over-expression in mice causes kidney disease.<ref name="Miyata_2007" /> Knockout in mice does not cause histological abnormalities.<ref name="Miyata_2007">{{cite journal | vauthors = Miyata T, Li M, Yu X, Hirayama N | title = Megsin gene: its genomic analysis, pathobiological functions, and therapeutic perspectives | journal = Current Genomics | volume = 8 | issue = 3 | pages = 203–208 | date = May 2007 | pmid = 18645605 | pmc = 2435355 | doi = 10.2174/138920207780833856 }}</ref>
|Mutations associated with [[Palmoplantar keratoderma|Nagashima-type Palmoplantar Keratosis]].<ref>{{cite journal | vauthors = Kubo A | title = Nagashima-type palmoplantar keratosis: a common Asian type caused by SERPINB7 protease inhibitor deficiency | journal = The Journal of Investigative Dermatology | volume = 134 | issue = 8 | pages = 2076–2079 | date = August 2014 | pmid = 25029323 | doi = 10.1038/jid.2014.156 | doi-access = free }}</ref>
| 18q21.3
|
|-
| [[SERPINB8]]
| [[SERPINB8|PI-8]]
|Intracellular
| Possible inhibitor of furin.<ref>{{cite journal | vauthors = Dahlen JR, Jean F, Thomas G, Foster DC, Kisiel W | title = Inhibition of soluble recombinant furin by human proteinase inhibitor 8 | journal = The Journal of Biological Chemistry | volume = 273 | issue = 4 | pages = 1851–1854 | date = January 1998 | pmid = 9442015 | doi = 10.1074/jbc.273.4.1851 | doi-access = free }}</ref>
|
|
| 18q21.3
|
|-
| [[SERPINB9]]
| [[SERPINB9|PI-9]]
|Intracellular
| Inhibitor of the cytotoxic granule protease granzyme B.<ref name="Sun_1996">{{cite journal | vauthors = Sun J, Bird CH, Sutton V, McDonald L, Coughlin PB, De Jong TA, Trapani JA, Bird PI | title = A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes | journal = The Journal of Biological Chemistry | volume = 271 | issue = 44 | pages = 27802–27809 | date = November 1996 | pmid = 8910377 | doi = 10.1074/jbc.271.44.27802 | doi-access = free }}</ref>
|Knockout in mice causes immune dysfunction.<ref>{{cite journal | vauthors = Zhang M, Park SM, Wang Y, Shah R, Liu N, Murmann AE, Wang CR, Peter ME, Ashton-Rickardt PG | title = Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules | journal = Immunity | volume = 24 | issue = 4 | pages = 451–461 | date = April 2006 | pmid = 16618603 | doi = 10.1016/j.immuni.2006.02.002 | doi-access = free }}</ref><ref name="Rizzitelli_2012">{{cite journal | vauthors = Rizzitelli A, Meuter S, Vega Ramos J, Bird CH, Mintern JD, Mangan MS, Villadangos J, Bird PI | title = Serpinb9 (Spi6)-deficient mice are impaired in dendritic cell-mediated antigen cross-presentation | journal = Immunology and Cell Biology | volume = 90 | issue = 9 | pages = 841–851 | date = October 2012 | pmid = 22801574 | doi = 10.1038/icb.2012.29 | s2cid = 39276036 }}</ref>
|
| 6p25
|
|-
| [[SERPINB10]]
| [[SERPINB10|Bomapin]]
|Intracellular
| Unknown<ref>{{cite journal | vauthors = Riewald M, Chuang T, Neubauer A, Riess H, Schleef RR | title = Expression of bomapin, a novel human serpin, in normal/malignant hematopoiesis and in the monocytic cell lines THP-1 and AML-193 | journal = Blood | volume = 91 | issue = 4 | pages = 1256–1262 | date = February 1998 | pmid = 9454755 | doi = 10.1182/blood.V91.4.1256 | doi-access = free }}</ref>
|Knockout in mice causes no obvious phenotype (C57/BL6; lab strain [https://www.ncbi.nlm.nih.gov/nuccore/47125085 BC069938]).
|
| 18q21.3
|
|-
| [[SERPINB11]]
| 
|Intracellular
| Unknown<ref name="serpinb112">{{cite journal | vauthors = Askew DJ, Cataltepe S, Kumar V, Edwards C, Pace SM, Howarth RN, Pak SC, Askew YS, Brömme D, Luke CJ, Whisstock JC, Silverman GA | title = SERPINB11 is a new noninhibitory intracellular serpin. Common single nucleotide polymorphisms in the scaffold impair conformational change | journal = The Journal of Biological Chemistry | volume = 282 | issue = 34 | pages = 24948–24960 | date = August 2007 | pmid = 17562709 | doi = 10.1074/jbc.M703182200 | doi-access = free }}</ref>
|Murine Serpinb11 is an active inhibitor whereas the human orthalogue is inactive.<ref name="serpinb112"/> Deficiency in ponies is associated with hoof wall separation disease.<ref name="Finno_2015">{{cite journal | vauthors = Finno CJ, Stevens C, Young A, Affolter V, Joshi NA, Ramsay S, Bannasch DL | title = SERPINB11 frameshift variant associated with novel hoof specific phenotype in Connemara ponies | journal = PLOS Genetics | volume = 11 | issue = 4 | article-number = e1005122 | date = April 2015 | pmid = 25875171 | pmc = 4395385 | doi = 10.1371/journal.pgen.1005122 | doi-access = free }}</ref>
|
| 18q21.3
|
|-
| [[SERPINB12]]
| [[Yukopin]]
|Intracellular
| Unknown<ref>{{cite journal | vauthors = Askew YS, Pak SC, Luke CJ, Askew DJ, Cataltepe S, Mills DR, Kato H, Lehoczky J, Dewar K, Birren B, Silverman GA | title = SERPINB12 is a novel member of the human ov-serpin family that is widely expressed and inhibits trypsin-like serine proteinases | journal = The Journal of Biological Chemistry | volume = 276 | issue = 52 | pages = 49320–49330 | date = December 2001 | pmid = 11604408 | doi = 10.1074/jbc.M108879200 | doi-access = free }}</ref>
|
|
| 18q21.3
|
|-
| [[SERPINB13]]
| [[SERPINB13|Hurpin]]/[[SERPINB13|Headpin]]
|Intracellular
| Inhibitor of papain-like cysteine proteases.<ref>{{cite journal | vauthors = Welss T, Sun J, Irving JA, Blum R, Smith AI, Whisstock JC, Pike RN, von Mikecz A, Ruzicka T, Bird PI, Abts HF | title = Hurpin is a selective inhibitor of lysosomal cathepsin L and protects keratinocytes from ultraviolet-induced apoptosis | journal = Biochemistry | volume = 42 | issue = 24 | pages = 7381–7389 | date = June 2003 | pmid = 12809493 | doi = 10.1021/bi027307q }}</ref>
|
|
| 18q21.3
|
|-
| [[SERPINC1]]
| [[Antithrombin]]
|Extracellular
| Inhibitor of [[coagulation]], specifically [[factor X]], [[factor IX]] and [[thrombin]].<ref name="Huntington_2006">{{cite journal | vauthors = Huntington JA | title = Shape-shifting serpins--advantages of a mobile mechanism | journal = Trends in Biochemical Sciences | volume = 31 | issue = 8 | pages = 427–435 | date = August 2006 | pmid = 16820297 | doi = 10.1016/j.tibs.2006.06.005 }}</ref>
|Knockouts in mice are lethal.<ref>{{cite journal | vauthors = Ishiguro K, Kojima T, Kadomatsu K, Nakayama Y, Takagi A, Suzuki M, Takeda N, Ito M, Yamamoto K, Matsushita T, Kusugami K, Muramatsu T, Saito H | title = Complete antithrombin deficiency in mice results in embryonic lethality | journal = The Journal of Clinical Investigation | volume = 106 | issue = 7 | pages = 873–878 | date = October 2000 | pmid = 11018075 | pmc = 517819 | doi = 10.1172/JCI10489 }}</ref>
|Deficiency results in thrombosis and other clotting disorders (serpinopathy).<ref name="Patnaik MM 2516">{{cite journal | vauthors = Patnaik MM, Moll S | title = Inherited antithrombin deficiency: a review | journal = Haemophilia | volume = 14 | issue = 6 | pages = 1229–1239 | date = November 2008 | pmid = 19141163 | doi = 10.1111/j.1365-2516.2008.01830.x | s2cid = 20768425 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Huntington JA | title = Serpin structure, function and dysfunction | journal = Journal of Thrombosis and Haemostasis | volume = 9 | issue = Suppl 1 | pages = 26–34 | date = July 2011 | pmid = 21781239 | doi = 10.1111/j.1538-7836.2011.04360.x | s2cid = 1020630 | doi-access = free }}</ref>
| 1q23-q21
|{{PDB2|2ANT}}, {{PDB2|2ZNH}}, {{PDB2|1AZX}}, {{PDB2|1TB6}}, {{PDB2|2GD4}}, {{PDB2|1T1F}}
|-
| [[SERPIND1]]
| [[Heparin cofactor II]]
|Extracellular
| Inhibitor of thrombin.<ref>{{cite journal | vauthors = Vicente CP, He L, Pavão MS, Tollefsen DM | title = Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice | journal = Blood | volume = 104 | issue = 13 | pages = 3965–3970 | date = December 2004 | pmid = 15315969 | doi = 10.1182/blood-2004-02-0598 | doi-access = free }}</ref>
|Knockouts in mice are lethal.<ref>{{cite journal | vauthors = Aihara K, Azuma H, Akaike M, Ikeda Y, Sata M, Takamori N, Yagi S, Iwase T, Sumitomo Y, Kawano H, Yamada T, Fukuda T, Matsumoto T, Sekine K, Sato T, Nakamichi Y, Yamamoto Y, Yoshimura K, Watanabe T, Nakamura T, Oomizu A, Tsukada M, Hayashi H, Sudo T, Kato S, Matsumoto T | title = Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice | journal = The Journal of Clinical Investigation | volume = 117 | issue = 6 | pages = 1514–1526 | date = June 2007 | pmid = 17549254 | pmc = 1878511 | doi = 10.1172/JCI27095 }}</ref>
|
| 22q11
|{{PDB2|1JMJ}}, {{PDB2|1JMO}}
|-
| [[SERPINE1]]
|  [[Plasminogen activator inhibitor 1]]
|Extracellular
| Inhibitor of thrombin, uPA and TPa.<ref name="Cale_2007">{{cite journal | vauthors = Cale JM, Lawrence DA | title = Structure-function relationships of plasminogen activator inhibitor-1 and its potential as a therapeutic agent | journal = Current Drug Targets | volume = 8 | issue = 9 | pages = 971–981 | date = September 2007 | pmid = 17896949 | doi = 10.2174/138945007781662337 }}</ref>
|
|
| 7q21.3-q22
|{{PDB2|1DVN}}, {{PDB2|1OC0}}
|-
| [[SERPINE2]]
| [[SERPINE2|Glia derived nexin]] / [[SERPINE2|Protease nexin I]]
|Extracellular
| Inhibitor of uPA and tPA.<ref name="Lino_2007">{{cite journal | vauthors = Lino MM, Atanasoski S, Kvajo M, Fayard B, Moreno E, Brenner HR, Suter U, Monard D | title = Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush | journal = The Journal of Neuroscience | volume = 27 | issue = 14 | pages = 3677–3685 | date = April 2007 | pmid = 17409231 | pmc = 6672422 | doi = 10.1523/JNEUROSCI.0277-07.2007 | doi-access = free }}</ref>
|Abnormal expression leads to male infertility.<ref>{{cite journal | vauthors = Murer V, Spetz JF, Hengst U, Altrogge LM, de Agostini A, Monard D | title = Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3029–3033 | date = March 2001 | pmid = 11248026 | pmc = 30601 | doi = 10.1073/pnas.051630698 | doi-access = free | bibcode = 2001PNAS...98.3029M }}</ref> Knockout in mice causes epilepsy.<ref name="Lüthi_1997">{{cite journal | vauthors = Lüthi A, Van der Putten H, Botteri FM, Mansuy IM, Meins M, Frey U, Sansig G, Portet C, Schmutz M, Schröder M, Nitsch C, Laurent JP, Monard D | title = Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation | journal = The Journal of Neuroscience | volume = 17 | issue = 12 | pages = 4688–4699 | date = June 1997 | pmid = 9169529 | pmc = 6573330 | doi = 10.1523/JNEUROSCI.17-12-04688.1997 | doi-access = free }}</ref>
|
| 2q33-q35
|{{PDB2|4DY0}}
|-
| [[SERPINF1]]
|  [[SERPINF1|Pigment epithelium derived factor]]
|Extracellular
| Non-inhibitory, potent anti-angiogenic molecule.<ref name="pedf2">{{cite journal | vauthors = Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, Cornwell ML, Pins MR, Borensztajn J, Crawford SE | title = Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas | journal = Nature Medicine | volume = 9 | issue = 6 | pages = 774–780 | date = June 2003 | pmid = 12740569 | doi = 10.1038/nm870 | s2cid = 5967666 }}</ref> PEDF has been reported to bind the glycosaminoglycan hyaluronan.<ref name="Becerra_2008">{{cite journal | vauthors = Becerra SP, Perez-Mediavilla LA, Weldon JE, Locatelli-Hoops S, Senanayake P, Notari L, Notario V, Hollyfield JG | title = Pigment epithelium-derived factor binds to hyaluronan. Mapping of a hyaluronan binding site | journal = The Journal of Biological Chemistry | volume = 283 | issue = 48 | pages = 33310–33320 | date = November 2008 | pmid = 18805795 | pmc = 2586245 | doi = 10.1074/jbc.M801287200 | doi-access = free }}</ref>
|Knockout in mice affects the vasculature and mass of the pancreas and the prostate.<ref name="pedf2"/> Promotes [[Notch signaling pathway|Notch–dependent]] renewal of adult [[Periventricular nucleus|periventricular]] neural stem cells.<ref name="PEDF2">{{cite journal | vauthors = Andreu-Agulló C, Morante-Redolat JM, Delgado AC, Fariñas I | title = Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone | journal = Nature Neuroscience | volume = 12 | issue = 12 | pages = 1514–1523 | date = December 2009 | pmid = 19898467 | doi = 10.1038/nn.2437 | s2cid = 5332822 }}</ref> Mutations in humans cause [[osteogenesis imperfecta]] type VI.<ref name="Homan_2011">{{cite journal | vauthors = Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, Bertin T, Napierala D, Morello R, Gibbs R, White L, Miki R, Cohn DH, Crawford S, Travers R, Glorieux FH, Lee B | title = Mutations in SERPINF1 cause osteogenesis imperfecta type VI | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 12 | pages = 2798–2803 | date = December 2011 | pmid = 21826736 | pmc = 3214246 | doi = 10.1002/jbmr.487 }}</ref>
|
| 17p13.3
|{{PDB2|1IMV}}
|-
| [[SERPINF2]]
| [[Alpha 2-antiplasmin|α2-antiplasmin]]
|Extracellular
| Inhibitor of plasmin, inhibitor of [[fibrinolysis]].<ref name="Wiman_1979">{{cite journal | vauthors = Wiman B, Collen D | title = On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin | journal = The Journal of Biological Chemistry | volume = 254 | issue = 18 | pages = 9291–9297 | date = September 1979 | pmid = 158022 | doi = 10.1016/S0021-9258(19)86843-6 | doi-access = free }}</ref>
|Knockouts in mice show increased mice show increased [[fibrinolysis]] but no bleeding disorder.<ref>{{cite journal | vauthors = Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M | title = Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding | journal = Blood | volume = 93 | issue = 7 | pages = 2274–2281 | date = April 1999 | pmid = 10090937 | doi = 10.1182/blood.V93.7.2274 }}</ref>
|Deficiency causes a rare bleeding disorder.<ref>{{cite journal | vauthors = Carpenter SL, Mathew P | title = Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance | journal = Haemophilia | volume = 14 | issue = 6 | pages = 1250–1254 | date = November 2008 | pmid = 19141165 | doi = 10.1111/j.1365-2516.2008.01766.x | s2cid = 205295156 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Favier R, Aoki N, de Moerloose P | title = Congenital alpha(2)-plasmin inhibitor deficiencies: a review | journal = British Journal of Haematology | volume = 114 | issue = 1 | pages = 4–10 | date = July 2001 | pmid = 11472338 | doi = 10.1046/j.1365-2141.2001.02845.x | s2cid = 71010865 | doi-access = free }}</ref>
| 17pter-p12
|{{PDB2|2R9Y}}
|-
| [[SERPING1]]
| [[C1-inhibitor|Complement 1-inhibitor]]
|Extracellular
| Inhibitor of C1 esterase.<ref name="Beinrohr_2007">{{cite journal | vauthors = Beinrohr L, Harmat V, Dobó J, Lörincz Z, Gál P, Závodszky P | title = C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease | journal = The Journal of Biological Chemistry | volume = 282 | issue = 29 | pages = 21100–21109 | date = July 2007 | pmid = 17488724 | doi = 10.1074/jbc.M700841200 | doi-access = free | bibcode = 2007JBiCh.28221100B | hdl = 10831/92835 | hdl-access = free }}</ref>
|
|Several polymorphisms associated with [[macular degeneration]]<ref>{{cite journal | vauthors = Mollnes TE, Jokiranta TS, Truedsson L, Nilsson B, Rodriguez de Cordoba S, Kirschfink M | title = Complement analysis in the 21st century | journal = Molecular Immunology | volume = 44 | issue = 16 | pages = 3838–3849 | date = September 2007 | pmid = 17768101 | doi = 10.1016/j.molimm.2007.06.150 | hdl-access = free | hdl = 10261/61732 }}</ref> and [[Hereditary angioedema|hereditary angeoedema]].<ref>{{cite journal | vauthors = Triggianese P, Chimenti MS, Toubi E, Ballanti E, Guarino MD, Perricone C, Perricone R | title = The autoimmune side of hereditary angioedema: insights on the pathogenesis | journal = Autoimmunity Reviews | volume = 14 | issue = 8 | pages = 665–669 | date = August 2015 | pmid = 25827463 | doi = 10.1016/j.autrev.2015.03.006 }}</ref>
| 11q11-q13.1
|{{PDB2|2OAY}}
|-
| [[SERPINH1]]
| [[47 kDa Heat shock protein]] (HSP47)
|Intracellular
| Non-inhibitory, molecular chaperone in collagen folding.<ref name="Mala_2010"/>
|Knockouts in mice are lethal.<ref>{{cite journal | vauthors = Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K | title = Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis | journal = The Journal of Cell Biology | volume = 150 | issue = 6 | pages = 1499–1506 | date = September 2000 | pmid = 10995453 | pmc = 2150697 | doi = 10.1083/jcb.150.6.1499 }}</ref>
|Mutation in humans causes severe [[osteogenesis imperfecta]].<ref>{{cite journal | vauthors = Marini JC, Reich A, Smith SM | title = Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation | journal = Current Opinion in Pediatrics | volume = 26 | issue = 4 | pages = 500–507 | date = August 2014 | pmid = 25007323 | pmc = 4183132 | doi = 10.1097/MOP.0000000000000117 }}</ref><ref>{{cite journal | vauthors = Byers PH, Pyott SM | title = Recessively inherited forms of osteogenesis imperfecta | journal = Annual Review of Genetics | volume = 46 | pages = 475–497 | date = 1 January 2012 | pmid = 23145505 | doi = 10.1146/annurev-genet-110711-155608 }}</ref>
| 11p15
|{{PDB2|4AXY}}
|-
| [[SERPINI1]]
| [[SERPINI1|Neuroserpin]]
|Extracellular
| Inhibitor of tPA, uPA and plasmin.<ref name="Osterwalder_1998">{{cite journal | vauthors = Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, Meins M, Sonderegger P | title = The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin | journal = The Journal of Biological Chemistry | volume = 273 | issue = 4 | pages = 2312–2321 | date = January 1998 | pmid = 9442076 | doi = 10.1074/jbc.273.4.2312 | doi-access = free }}</ref>
|
|Mutation causes [[Familial encephalopathy with neuroserpin inclusion bodies|FENIB]] dementia (serpinopathy).<ref>{{cite journal | vauthors = Crowther DC | title = Familial conformational diseases and dementias | journal = Human Mutation | volume = 20 | issue = 1 | pages = 1–14 | date = July 2002 | pmid = 12112652 | doi = 10.1002/humu.10100 | s2cid = 22326349 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Belorgey D, Hägglöf P, Karlsson-Li S, Lomas DA | title = Protein misfolding and the serpinopathies | journal = Prion | volume = 1 | issue = 1 | pages = 15–20 | date = 1 March 2007 | pmid = 19164889 | pmc = 2633702 | doi = 10.4161/pri.1.1.3974 }}</ref>
| 3q26
|{{PDB2|1JJO}}, {{PDB2|3FGQ}}, {{PDB2|3F5N}}, {{PDB2|3F02}}
|-
| [[SERPINI2]]
| [[SERPINI2|Pancpin]]
|Extracellular
| Unknown<ref name="pancipin">{{cite journal | vauthors = Ozaki K, Nagata M, Suzuki M, Fujiwara T, Miyoshi Y, Ishikawa O, Ohigashi H, Imaoka S, Takahashi E, Nakamura Y | title = Isolation and characterization of a novel human pancreas-specific gene, pancpin, that is down-regulated in pancreatic cancer cells | journal = Genes, Chromosomes & Cancer | volume = 22 | issue = 3 | pages = 179–185 | date = July 1998 | pmid = 9624529 | doi = 10.1002/(SICI)1098-2264(199807)22:3<179::AID-GCC3>3.0.CO;2-T | s2cid = 9525421 }}</ref>
|Deficiency in mice causes pancreatic insufficiency via [[Centroacinar cell|acinar cell]] loss.<ref name="Loftus_2005">{{cite journal | vauthors = Loftus SK, Cannons JL, Incao A, Pak E, Chen A, Zerfas PM, Bryant MA, Biesecker LG, Schwartzberg PL, Pavan WJ | title = Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency | journal = PLOS Genetics | volume = 1 | issue = 3 | article-number = e38 | date = September 2005 | pmid = 16184191 | pmc = 1231717 | doi = 10.1371/journal.pgen.0010038 | doi-access = free }}</ref>
|
| 3q26
|
|}

====Specialised mammalian serpins====
Many [[mammal]]ian serpins have been identified that share no obvious orthology with a human serpin counterpart. Examples include numerous [[rodent]] serpins (particularly some of the [[murine]] intracellular serpins) as well as the [[uterine serpin]]s. The term uterine serpin refers to members of the serpin A clade that are encoded by the SERPINA14 gene. Uterine serpins are produced by the [[endometrium]] of a restricted group of mammals in the [[Laurasiatheria]] clade under the influence of [[progesterone]] or [[estrogen]].<ref name="Padua_2010">{{cite journal | vauthors = Padua MB, Kowalski AA, Cañas MY, Hansen PJ | title = The molecular phylogeny of uterine serpins and its relationship to evolution of placentation | journal = FASEB Journal | volume = 24 | issue = 2 | pages = 526–537 | date = February 2010 | pmid = 19825977 | doi = 10.1096/fj.09-138453 | doi-access = free | s2cid = 9248169 }}</ref> They are probably not functional proteinase inhibitors and may function during pregnancy to inhibit maternal immune responses against the [[conceptus]] or to participate in transplacental transport.<ref name="Padua_Hansen_2010">{{cite journal | vauthors = Padua MB, Hansen PJ | title = Evolution and function of the uterine serpins (SERPINA14) | journal = American Journal of Reproductive Immunology | volume = 64 | issue = 4 | pages = 265–274 | date = October 2010 | pmid = 20678169 | doi = 10.1111/j.1600-0897.2010.00901.x | doi-access = free }}</ref>

===Insect===
The ''[[Drosophila melanogaster]]'' genome contains 29&nbsp;serpin encoding genes. Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and three in serpin clade K with the remaining twelve classified as orphan serpins not belonging to any clade.<ref name="Reichhart_2005" >{{cite journal | vauthors = Reichhart JM | title = Tip of another iceberg: Drosophila serpins | journal = Trends in Cell Biology | volume = 15 | issue = 12 | pages = 659–665 | date = December 2005 | pmid = 16260136 | doi = 10.1016/j.tcb.2005.10.001 }}</ref> The clade classification system is difficult to use for ''Drosophila'' serpins and instead a nomenclature system has been adopted that is based on the position of serpin genes on the ''Drosophila'' [[chromosome]]s. Thirteen of the ''Drosophila'' serpins occur as isolated genes in the genome (including Serpin-27A, see below), with the remaining 16 organised into five gene clusters that occur at chromosome positions 28D (2&nbsp;serpins), 42D (5&nbsp;serpins), 43A (4&nbsp;serpins), 77B (3&nbsp;serpins) and 88E (2&nbsp;serpins).<ref name="Reichhart_2005"/><ref name="Tang_2008">{{cite journal | vauthors = Tang H, Kambris Z, Lemaitre B, Hashimoto C | title = A serpin that regulates immune melanization in the respiratory system of Drosophila | journal = Developmental Cell | volume = 15 | issue = 4 | pages = 617–626 | date = October 2008 | pmid = 18854145 | pmc = 2671232 | doi = 10.1016/j.devcel.2008.08.017 }}</ref><ref name="Scherfer_2008">{{cite journal | vauthors = Scherfer C, Tang H, Kambris Z, Lhocine N, Hashimoto C, Lemaitre B | title = Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation | journal = Developmental Biology | volume = 323 | issue = 2 | pages = 189–196 | date = November 2008 | pmid = 18801354 | doi = 10.1016/j.ydbio.2008.08.030 | doi-access = free }}</ref>

Studies on ''Drosophila'' serpins reveal that Serpin-27A inhibits the Easter protease (the final protease in the Nudel, Gastrulation Defective, Snake and Easter proteolytic cascade) and thus controls [[Regional specification#Dorsal/ventral axis|dorsoventral patterning]]. Easter functions to cleave Spätzle (a chemokine-type ligand), which results in [[Toll-like receptor|toll-mediated]] signaling. As well as its central role in embryonic patterning, toll signaling is also important for the [[Innate immune system#Invertebrates|innate immune response]] in insects. Accordingly, serpin-27A also functions to control the insect immune response.<ref name="Hashimoto 945–950"/><ref>{{cite journal | vauthors = Rushlow C | title = Dorsoventral patterning: a serpin pinned down at last | journal = Current Biology | volume = 14 | issue = 1 | pages = R16–R18 | date = January 2004 | pmid = 14711428 | doi = 10.1016/j.cub.2003.12.015 | doi-access = free | bibcode = 2004CBio...14..R16R }}</ref><ref>{{cite journal | vauthors = Ligoxygakis P, Roth S, Reichhart JM | title = A serpin regulates dorsal-ventral axis formation in the Drosophila embryo | journal = Current Biology | volume = 13 | issue = 23 | pages = 2097–2102 | date = December 2003 | pmid = 14654000 | doi = 10.1016/j.cub.2003.10.062 | doi-access = free | bibcode = 2003CBio...13.2097L }}</ref> In ''[[Tenebrio molitor]]'' (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade.<ref name="Jiang_2011">{{cite journal | vauthors = Jiang R, Zhang B, Kurokawa K, So YI, Kim EH, Hwang HO, Lee JH, Shiratsuchi A, Zhang J, Nakanishi Y, Lee HS, Lee BL | title = 93-kDa twin-domain serine protease inhibitor (Serpin) has a regulatory function on the beetle Toll proteolytic signaling cascade | journal = The Journal of Biological Chemistry | volume = 286 | issue = 40 | pages = 35087–35095 | date = October 2011 | pmid = 21862574 | pmc = 3186399 | doi = 10.1074/jbc.M111.277343 | doi-access = free }}</ref>

Serpins have been found in [[tick]] saliva, suppressing [[T lymphocyte]] production and inhibiting expression of [[TNF-α]], [[IFN-γ]], and [[Interleukin 6|IL-6]].<ref>{{Cite journal |last1=Denisov |first1=Stepan S. |last2=Dijkgraaf |first2=Ingrid |date=2021-10-13 |title=Immunomodulatory Proteins in Tick Saliva From a Structural Perspective |journal=Frontiers in Cellular and Infection Microbiology |language=English |volume=11 |article-number=769574 |doi=10.3389/fcimb.2021.769574 |doi-access=free |pmid=34722347 |pmc=8548845 |issn=2235-2988}}</ref>

===Nematode===
The genome of the [[nematode]] worm ''[[Caenorhabditis elegans|C. elegans]]'' contains 9&nbsp;serpins, all of which lack signal sequences and so are likely intracellular.<ref name="elegans1">{{cite journal | vauthors = Pak SC, Kumar V, Tsu C, Luke CJ, Askew YS, Askew DJ, Mills DR, Brömme D, Silverman GA | title = SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins | journal = The Journal of Biological Chemistry | volume = 279 | issue = 15 | pages = 15448–15459 | date = April 2004 | pmid = 14739286 | doi = 10.1074/jbc.M400261200 | doi-access = free }}</ref> However, only&nbsp;5 of these serpins appear to function as protease inhibitors.<ref name="elegans1"/> One, SRP-6, performs a protective function and guards against stress-induced [[calpain]]-associated lysosomal disruption. Further, SRP-6 inhibits lysosomal cysteine proteases released after lysosomal rupture. Accordingly, worms lacking SRP-6 are sensitive to stress. Most notably, SRP-6 knockout worms die when placed in water (the hypo-osmotic stress lethal phenotype or Osl). It has therefore been suggested that lysosomes play a general and controllable role in determining cell fate.<ref>{{cite journal | vauthors = Luke CJ, Pak SC, Askew YS, Naviglia TL, Askew DJ, Nobar SM, Vetica AC, Long OS, Watkins SC, Stolz DB, Barstead RJ, Moulder GL, Brömme D, Silverman GA | title = An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury | journal = Cell | volume = 130 | issue = 6 | pages = 1108–1119 | date = September 2007 | pmid = 17889653 | pmc = 2128786 | doi = 10.1016/j.cell.2007.07.013 }}</ref>

===Plant===
[[Plant]] serpins were amongst the first members of the superfamily that were identified.<ref>{{cite journal | vauthors = Hejgaard J, Rasmussen SK, Brandt A, SvendsenI | title = Sequence homology between barley endosperm protein Z and protease inhibitors of the alpha-1-antitrypsin family | journal = FEBS Lett. | volume = 180 | issue = 1 | year = 1985 | pages = 89–94 | doi = 10.1016/0014-5793(85)80238-6 | s2cid = 84790014 | doi-access = free | bibcode = 1985FEBSL.180...89H }}</ref> The serpin barley protein Z is highly abundant in barley grain, and one of the major protein components in beer. The genome of the model plant, ''[[Arabidopsis thaliana]]'' contain 18&nbsp;serpin-like genes, although only&nbsp;8 of these are full-length serpin sequences.

Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases ''in vitro'', the best-studied example being barley serpin Zx (BSZx), which is able to inhibit trypsin and chymotrypsin as well as several blood coagulation factors.<ref>{{cite journal | vauthors = Dahl SW, Rasmussen SK, Petersen LC, Hejgaard J | title = Inhibition of coagulation factors by recombinant barley serpin BSZx | journal = FEBS Letters | volume = 394 | issue = 2 | pages = 165–168 | date = September 1996 | pmid = 8843156 | doi = 10.1016/0014-5793(96)00940-4 | doi-access = free | bibcode = 1996FEBSL.394..165D }}</ref> However, close relatives of chymotrypsin-like serine proteases are absent in plants. The RCL of several serpins from wheat grain and rye contain poly-Q repeat sequences similar to those present in the [[prolamin]] storage proteins of the endosperm.<ref>{{cite journal | vauthors = Hejgaard J | title = Inhibitory serpins from rye grain with glutamine as P1 and P2 residues in the reactive center | journal = FEBS Letters | volume = 488 | issue = 3 | pages = 149–153 | date = January 2001 | pmid = 11163762 | doi = 10.1016/S0014-5793(00)02425-X | s2cid = 27933086 | doi-access = free | bibcode = 2001FEBSL.488..149H }}</ref><ref>{{cite journal | vauthors = Ostergaard H, Rasmussen SK, Roberts TH, Hejgaard J | title = Inhibitory serpins from wheat grain with reactive centers resembling glutamine-rich repeats of prolamin storage proteins. Cloning and characterization of five major molecular forms | journal = The Journal of Biological Chemistry | volume = 275 | issue = 43 | pages = 33272–33279 | date = October 2000 | pmid = 10874043 | doi = 10.1074/jbc.M004633200 | doi-access = free }}</ref> It has therefore been suggested that plant serpins may function to inhibit proteases from insects or microbes that would otherwise digest grain storage proteins. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin (CmPS-1)<ref name="plant">{{cite journal | vauthors = Yoo BC, Aoki K, Xiang Y, Campbell LR, Hull RJ, Xoconostle-Cázares B, Monzer J, Lee JY, Ullman DE, Lucas WJ | title = Characterization of cucurbita maxima phloem serpin-1 (CmPS-1). A developmentally regulated elastase inhibitor | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 35122–35128 | date = November 2000 | pmid = 10960478 | doi = 10.1074/jbc.M006060200 | doi-access = free }}</ref> and cucumber plants.<ref>{{cite journal | vauthors = la Cour Petersen M, Hejgaard J, Thompson GA, Schulz A | title = Cucurbit phloem serpins are graft-transmissible and appear to be resistant to turnover in the sieve element-companion cell complex | journal = Journal of Experimental Botany | volume = 56 | issue = 422 | pages = 3111–3120 | date = December 2005 | pmid = 16246856 | doi = 10.1093/jxb/eri308 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Roberts TH, Hejgaard J | title = Serpins in plants and green algae | journal = Functional & Integrative Genomics | volume = 8 | issue = 1 | pages = 1–27 | date = February 2008 | pmid = 18060440 | doi = 10.1007/s10142-007-0059-2 | s2cid = 22960858 }}</ref> Although an inverse correlation between up-regulation of CmPS-1 expression and aphid survival was observed, ''in vitro'' feeding experiments revealed that recombinant CmPS-1 did not appear to affect insect survival.<ref name="plant"/>

Alternative roles and protease targets for plant serpins have been proposed. The ''Arabidopsis'' serpin, AtSerpin1 (At1g47710; {{PDB2|3LE2}}), mediates set-point control over programmed cell death by targeting the 'Responsive to Desiccation-21' (RD21) papain-like cysteine protease.<ref name="Lampl_2010"/><ref>{{cite journal | vauthors = Lampl N, Alkan N, Davydov O, Fluhr R | title = Set-point control of RD21 protease activity by AtSerpin1 controls cell death in Arabidopsis | journal = The Plant Journal | volume = 74 | issue = 3 | pages = 498–510 | date = May 2013 | pmid = 23398119 | doi = 10.1111/tpj.12141 | doi-access = free | bibcode = 2013PlJ....74..498L }}</ref> AtSerpin1 also inhibits [[metacaspase]]-like proteases ''in vitro''.<ref name="Vercammen_2006"/> Two other ''Arabidopsis'' serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage.<ref>{{cite journal | vauthors = Ahn JW, Atwell BJ, Roberts TH | title = Serpin genes AtSRP2 and AtSRP3 are required for normal growth sensitivity to a DNA alkylating agent in Arabidopsis | journal = BMC Plant Biology | volume = 9 | article-number = 52 | date = May 2009 | issue = 1 | pmid = 19426562 | pmc = 2689219 | doi = 10.1186/1471-2229-9-52 | doi-access = free | bibcode = 2009BMCPB...9...52A }}</ref>

===Fungal===
A single [[Fungus|fungal]] serpin has been characterized to date: {{proper name|celpin}} from ''[[Neocallimastigomycota|Piromyces]]'' [[spp.]] strain E2. ''Piromyces'' is a [[genus]] of anaerobic fungi found in the gut of ruminants and is important for digesting plant material. {{proper name|Celpin}} is predicted to be inhibitory and contains two N-terminal [[dockerin]] domains in addition to its serpin domain. Dockerins are commonly found in proteins that localise to the fungal [[cellulosome]], a large extracellular multiprotein complex that breaks down cellulose.<ref name="Steenbakkers_2008"/> It is therefore suggested that {{proper name|celpin}} may protect the cellulosome against plant proteases. Certain bacterial serpins similarly localize to the cellulosome.<ref name="thermo2"/>

===Prokaryotic===
Predicted serpin genes are sporadically distributed in [[prokaryote]]s. ''In vitro'' studies on some of these molecules have revealed that they are able to inhibit proteases, and it is suggested that they function as inhibitors ''in vivo''. Several prokaryote serpins are found in [[extremophile]]s. Accordingly, and in contrast to mammalian serpins, these molecules possess elevated resistance to heat denaturation.<ref>{{cite journal | vauthors = Irving JA, Cabrita LD, Rossjohn J, Pike RN, Bottomley SP, Whisstock JC | title = The 1.5 A crystal structure of a prokaryote serpin: controlling conformational change in a heated environment | journal = Structure | volume = 11 | issue = 4 | pages = 387–397 | date = April 2003 | pmid = 12679017 | doi = 10.1016/S0969-2126(03)00057-1 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Fulton KF, Buckle AM, Cabrita LD, Irving JA, Butcher RE, Smith I, Reeve S, Lesk AM, Bottomley SP, Rossjohn J, Whisstock JC | title = The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition | journal = The Journal of Biological Chemistry | volume = 280 | issue = 9 | pages = 8435–8442 | date = March 2005 | pmid = 15590653 | doi = 10.1074/jbc.M410206200 | doi-access = free }}</ref> The precise role of most bacterial serpins remains obscure, although ''[[Clostridium thermocellum]]'' serpin localises to the [[cellulosome]]. It is suggested that the role of cellulosome-associated serpins may be to prevent unwanted protease activity against the cellulosome.<ref name="thermo2">{{cite journal | vauthors = Kang S, Barak Y, Lamed R, Bayer EA, Morrison M | title = The functional repertoire of prokaryote cellulosomes includes the serpin superfamily of serine proteinase inhibitors | journal = Molecular Microbiology | volume = 60 | issue = 6 | pages = 1344–1354 | date = June 2006 | pmid = 16796673 | doi = 10.1111/j.1365-2958.2006.05182.x | s2cid = 23738804 | doi-access = free }}</ref>

===Viral===
Serpins are also expressed by [[virus]]es as a way to evade the host's immune defense.<ref name="Turner_2002">{{cite journal | vauthors = Turner PC, Moyer RW | title = Poxvirus immune modulators: functional insights from animal models | journal = Virus Research | volume = 88 | issue = 1–2 | pages = 35–53 | date = September 2002 | pmid = 12297326 | doi = 10.1016/S0168-1702(02)00119-3 }}</ref> In particular, serpins expressed by [[Poxviridae|pox viruses]], including [[Cowpox|cow pox]] (vaccinia) and [[Rabbitpox|rabbit pox]] (myxoma), are of interest because of their potential use as novel therapeutics for immune and inflammatory disorders as well as transplant therapy.<ref name="Richardson_2006">{{cite journal | vauthors = Richardson J, Viswanathan K, Lucas A | title = Serpins, the vasculature, and viral therapeutics | journal = Frontiers in Bioscience | volume = 11 | pages = 1042–1056 | date = January 2006 | pmid = 16146796 | doi = 10.2741/1862 | doi-access = free }}</ref><ref name="Jiang_2007">{{cite journal | vauthors = Jiang J, Arp J, Kubelik D, Zassoko R, Liu W, Wise Y, Macaulay C, Garcia B, McFadden G, Lucas AR, Wang H | title = Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment | journal = Transplantation | volume = 84 | issue = 9 | pages = 1158–1167 | date = November 2007 | pmid = 17998872 | doi = 10.1097/01.tp.0000286099.50532.b0 | s2cid = 20168458 | doi-access = free }}</ref> Serp1 suppresses the TLR-mediated innate immune response and allows indefinite cardiac [[Allotransplantation|allograft]] survival in rats.<ref name="Richardson_2006"/><ref name="Dai_2003">{{cite journal | vauthors = Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas A | title = Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury | journal = The Journal of Biological Chemistry | volume = 278 | issue = 20 | pages = 18563–18572 | date = May 2003 | pmid = 12637546 | doi = 10.1074/jbc.M209683200 | doi-access = free }}</ref> Crma and Serp2 are both cross-class inhibitors and target both serine (granzyme B; albeit weakly) and cysteine proteases (caspase&nbsp;1 and caspase&nbsp;8).<ref name="Turner_1999">{{cite journal | vauthors = Turner PC, Sancho MC, Thoennes SR, Caputo A, Bleackley RC, Moyer RW | title = Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1beta-converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus-infected cells | journal = Journal of Virology | volume = 73 | issue = 8 | pages = 6394–6404 | date = August 1999 | pmid = 10400732 | pmc = 112719 | doi = 10.1128/JVI.73.8.6394-6404.1999 }}</ref><ref name="Munuswamy-Ramanujam_2006">{{cite journal | vauthors = Munuswamy-Ramanujam G, Khan KA, Lucas AR | title = Viral anti-inflammatory reagents: the potential for treatment of arthritic and vasculitic disorders | journal = Endocrine, Metabolic & Immune Disorders Drug Targets | volume = 6 | issue = 4 | pages = 331–343 | date = December 2006 | pmid = 17214579 | doi = 10.2174/187153006779025720 }}</ref> In comparison to their mammalian counterparts, viral serpins contain significant deletions of elements of secondary structure. Specifically, crmA lacks the D-helix as well as significant portions of the A- and E-helices.<ref name="Renatus_2000">{{cite journal | vauthors = Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS | title = Crystal structure of the apoptotic suppressor CrmA in its cleaved form | journal = Structure | volume = 8 | issue = 7 | pages = 789–797 | date = July 2000 | pmid = 10903953 | doi = 10.1016/S0969-2126(00)00165-9 | doi-access = free }}</ref>

== References ==
{{Portal|Biology}}
{{reflist}}

== External links ==
{{Wiktionary}}
* {{PDB Molecule of the Month|53|Serpin}}
* [http://merops.sanger.ac.uk/cgi-bin/famsum?family=I4 Merops protease inhibitor claudication (Family I4)] {{Webarchive|url=https://web.archive.org/web/20161208210702/http://merops.sanger.ac.uk/cgi-bin/famsum?family=I4 |date=8 December 2016 }}
* {{MeshName|Serpins}}
*[https://whisstock-lab.med.monash.edu.au/ James Whisstock laboratory] at [[Monash University]]
*[http://huntingtonlab.cimr.cam.ac.uk/ Jim Huntington laboratory] {{Webarchive|url=https://web.archive.org/web/20161030180728/http://huntingtonlab.cimr.cam.ac.uk/ |date=30 October 2016 }} at [[University of Cambridge]]
*[https://web.archive.org/web/20161121042631/https://www.med.unc.edu/pharm/people/joint-faculty/frank-church-1 Frank Church laboratory] at [[University of North Carolina at Chapel Hill]]
*[https://web.archive.org/web/20060504050207/http://pharm.kuleuven.be/biotech/index.htm Paul Declerck laboratory] at [[Katholieke Universiteit Leuven]]
*[https://sydney.edu.au/agriculture/academic_staff/tom.roberts.php Tom Roberts laboratory] at [[University of Sydney]]
*[http://www.weizmann.ac.il/plants/fluhr/ Robert Fluhr laboratory] {{Webarchive|url=https://web.archive.org/web/20141019074048/http://www.weizmann.ac.il/plants/fluhr/ |date=19 October 2014 }} at [[Weizmann Institute of Science]]
*[http://bcmg.com.uic.edu/faculty/gettins_peter.html Peter Gettins laboratory] at [[University of Illinois at Chicago]]
* {{PDBe-KB2|P01009|Human Alpha-1-antitrypsin}}

{{Serpins}}

[[Category:Serine protease inhibitors|*]]
[[Category:Protein families]]