View source for Plasmin

{{Short description|Enzyme in human blood that degrades clots and other proteins}}
{{Infobox_gene}}
'''Plasmin''' is an important [[enzyme]] ({{EC number|3.4.21.7}}) present in [[blood]] that degrades many [[blood plasma]] proteins, including [[fibrin]] [[thrombus|clots]]. The degradation of fibrin is termed [[fibrinolysis]].  In humans, the plasmin protein (in the [[zymogen]] form of '''plasminogen''') is encoded by the ''PLG'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: plasminogen | url =https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5340 }}</ref>

== Function ==

[[File:Fibrinolysis.svg|thumb|left|300px|Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.]]

Plasmin is a [[serine protease]] that acts to dissolve [[fibrin]] blood clots. Apart from fibrinolysis, plasmin [[proteolysis|proteolyses]] proteins in various other systems: It activates [[collagenase]]s, some mediators of the [[complement system]], and weakens the wall of the [[Graafian follicle]], leading to [[ovulation]]. Plasmin is also integrally involved in inflammation.<ref>{{cite journal | vauthors = Atsev S, Tomov N | title = Using antifibrinolytics to tackle neuroinflammation | journal = Neural Regeneration Research | volume = 15 | issue = 12 | pages = 2203–2206 | date = December 2020 | pmid = 32594031 | pmc = 7749481 | doi = 10.4103/1673-5374.284979 | doi-access = free }}</ref>  It cleaves [[fibrin]], [[fibronectin]], [[thrombospondin]], laminin, and [[von Willebrand factor]]. Plasmin, like [[trypsin]], belongs to the family of [[serine protease]]s.

Plasmin is released as a [[zymogen]] called '''plasminogen''' (PLG) from the liver into the systemic circulation.  Two major glycoforms of plasminogen are present in humans - type I plasminogen contains two glycosylation moieties (N-linked to N289 and O-linked to T346), whereas type II plasminogen contains only a single O-linked sugar (O-linked to T346).  Type II plasminogen is preferentially recruited to the cell surface over the type I glycoform.  Conversely, type I plasminogen appears more readily recruited to blood clots.

In circulation, plasminogen adopts a closed, activation-resistant conformation.  Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of [[enzymes]], including [[tissue plasminogen activator]] (tPA), [[urokinase]] plasminogen activator (uPA), [[kallikrein]], and [[factor XII]] (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator. [[urokinase receptor|Urokinase plasminogen activator receptor]] (uPAR) is a cofactor for plasminogen activation by urokinase plasminogen activator.  The conversion of plasminogen to plasmin involves the cleavage of the peptide bond between Arg-561 and Val-562.<ref name="entrez"/><ref name="pmid6216475">{{cite journal | vauthors = Miyata T, Iwanaga S, Sakata Y, Aoki N | title = Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 20 | pages = 6132–6136 | date = October 1982 | pmid = 6216475 | pmc = 347073 | doi = 10.1073/pnas.79.20.6132 | doi-access = free | bibcode = 1982PNAS...79.6132M }}</ref><ref name="pmid">{{cite journal | vauthors = Forsgren M, Råden B, Israelsson M, Larsson K, Hedén LO | title = Molecular cloning and characterization of a full-length cDNA clone for human plasminogen | journal = FEBS Letters | volume = 213 | issue = 2 | pages = 254–260 | date = March 1987 | pmid = 3030813 | doi = 10.1016/0014-5793(87)81501-6 | s2cid = 9075872 | doi-access = free | bibcode = 1987FEBSL.213..254F }}</ref><ref name=Law_2012>{{cite journal | vauthors = Law RH, Caradoc-Davies T, Cowieson N, Horvath AJ, Quek AJ, Encarnacao JA, Steer D, Cowan A, Zhang Q, Lu BG, Pike RN, Smith AI, Coughlin PB, Whisstock JC | display-authors = 6 | title = The X-ray crystal structure of full-length human plasminogen | journal = Cell Reports | volume = 1 | issue = 3 | pages = 185–190 | date = March 2012 | pmid = 22832192 | doi = 10.1016/j.celrep.2012.02.012 | doi-access = free }}</ref>

Plasmin cleavage produces [[angiostatin]].

== Mechanism of plasminogen activation ==

Full length  plasminogen comprises seven domains.  In addition to a  C-terminal chymotrypsin-like serine protease domain, plasminogen contains an [[PAN domain|N-terminal Pan Apple domain (PAp)]] together with five [[Kringle domain|Kringle domains (KR1-5)]]. The Pan-Apple domain contains important determinants for maintaining plasminogen in the closed form, and the kringle domains are responsible for binding to lysine residues present in receptors and substrates.

The X-ray crystal structure of closed plasminogen reveals that the PAp and SP domains maintain the closed conformation through interactions made throughout the kringle array .<ref name="Law_2012"/> Chloride ions further bridge the PAp / KR4 and SP / KR2 interfaces, explaining the physiological role of serum chloride in stabilizing the closed conformer. The structural studies also reveal that differences in glycosylation alter the position of KR3.  These data help explain the functional differences between the type I and type II  plasminogen glycoforms.{{citation needed|date=February 2019}}

In closed plasminogen, access to the activation bond (R561/V562) targeted for cleavage by tPA and uPA is blocked through the position of the KR3/KR4 linker sequence and the O-linked sugar on T346. The position of KR3 may also hinder access to the [[activation loop]]. The Inter-domain interactions also block all kringle ligand-binding sites apart from that of KR-1, suggesting that the latter domain governs pro-enzyme recruitment to targets. Analysis of an intermediate plasminogen structure suggests that plasminogen conformational change to the open form is initiated through KR-5 transiently peeling away from the PAp domain. These movements expose the KR5 lysine-binding site to potential binding partners, and suggest a requirement for spatially distinct lysine residues in eliciting plasminogen recruitment and conformational change respectively.<ref name="Law_2012"/>

== Mechanism of plasmin inactivation ==

{{Unreferenced section|date=November 2016}}

Plasmin is inactivated by proteins such as [[Alpha-2-Macroglobulin|α2-macroglobulin]] and [[Alpha 2-antiplasmin|α2-antiplasmin]].<ref>{{cite journal | vauthors = Wu G, Quek AJ, Caradoc-Davies TT, Ekkel SM, Mazzitelli B, Whisstock JC, Law RH | title = Structural studies of plasmin inhibition | journal = Biochemical Society Transactions | volume = 47 | issue = 2 | pages = 541–557 | date = April 2019 | pmid = 30837322 | doi = 10.1042/bst20180211 | s2cid = 73463150 }}</ref> The mechanism of plasmin inactivation involves the cleavage of an α2-macroglobulin at the bait region (a segment of the aM that is particularly susceptible to proteolytic cleavage) by plasmin. This initiates a conformational change such that the α2-macroglobulin collapses about the plasmin. In the resulting α2-macroglobulin-plasmin complex, the active site of plasmin is [[Steric effects#Steric hindrance|sterically]] shielded, thus substantially decreasing the plasmin's access to protein substrates. Two additional events occur as a consequence of bait region cleavage, namely (i) a h-cysteinyl-g-glutamyl thiol ester of the α2-macroglobulin becomes highly reactive and (ii) a major conformational change exposes a conserved [[COOH-terminal]] receptor binding domain. The exposure of this receptor binding domain allows the α2-macroglobulin protease complex to bind to clearance receptors and be removed from circulation.

== Pathology ==

Plasmin deficiency may lead to [[thrombosis]], as the clots are not adequately degraded. Plasminogen deficiency in mice leads to defective liver repair,<ref>{{cite journal | vauthors = Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL | title = Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 26 | pages = 15143–15148 | date = December 1999 | pmid = 10611352 | pmc = 24787 | doi = 10.1073/pnas.96.26.15143 | doi-access = free | bibcode = 1999PNAS...9615143B }}</ref> defective wound healing, reproductive abnormalities.<ref>{{cite journal | vauthors = Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K | title = Impaired wound healing in mice with a disrupted plasminogen gene | journal = Nature Medicine | volume = 2 | issue = 3 | pages = 287–292 | date = March 1996 | pmid = 8612226 | doi = 10.1038/nm0396-287 | s2cid = 29981847 }}
</ref>
<ref>{{cite journal | vauthors = Ploplis VA, Carmeliet P, Vazirzadeh S, Van Vlaenderen I, Moons L, Plow EF, Collen D | title = Effects of disruption of the plasminogen gene on thrombosis, growth, and health in mice | journal = Circulation | volume = 92 | issue = 9 | pages = 2585–2593 | date = November 1995 | pmid = 7586361 | doi = 10.1161/01.cir.92.9.2585 | doi-access =  }}
</ref>

In humans, a rare disorder called [[plasminogen deficiency type I]] ({{OMIM|217090}}) is caused by mutations of the ''PLG'' gene and is often manifested by [[ligneous conjunctivitis]].<ref>{{cite journal | vauthors = Schuster V, Hügle B, Tefs K | title = Plasminogen deficiency | journal = Journal of Thrombosis and Haemostasis | volume = 5 | issue = 12 | pages = 2315–2322 | date = December 2007 | pmid = 17900274 | doi = 10.1111/j.1538-7836.2007.02776.x | doi-access = free }}</ref>

A rare [[missense mutation]] within the kringle 3 domain of plasminogen, resulting in a novel type of dysplasminogenemia, represents the molecular basis of a subtype of hereditary angioedema with normal C1-inhibitor;<ref name="Dewald">{{cite journal | vauthors = Dewald G | title = A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor | journal = Biochemical and Biophysical Research Communications | volume = 498 | issue = 1 | pages = 193–198 | date = March 2018 | pmid = 29548426 | doi = 10.1016/j.bbrc.2017.12.060 | bibcode = 2018BBRC..498..193D }}
</ref> the mutation creates a new lysine-binding site within kringle 3 and alters the glycosylation of plasminogen.<ref name="Dewald" /> The mutant plasminogen protein has been shown to be a highly efficient kininogenase that directly releases bradykinin from high- and low-molecular-weight kininogen.<ref>{{cite journal | vauthors = Dickeson SK, Kumar S, Sun MF, Mohammed BM, Phillips DR, Whisstock JC, Quek AJ, Feener EP, Law RH, Gailani D | display-authors = 6 | title = A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen | journal = Blood | volume = 139 | issue = 18 | pages = 2816–2829 | date = May 2022 | pmid = 35100351 | doi = 10.1182/blood.2021012945 | pmc = 9074402 | doi-access = free }}
</ref>

== Interactions ==

Plasmin has been shown to [[Protein–protein interaction|interact]] with [[Thrombospondin 1]],<ref name=pmid6438154>{{cite journal | vauthors = Silverstein RL, Leung LL, Harpel PC, Nachman RL | title = Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator | journal = The Journal of Clinical Investigation | volume = 74 | issue = 5 | pages = 1625–1633 | date = November 1984 | pmid = 6438154 | pmc = 425339 | doi = 10.1172/JCI111578 }}</ref><ref name=pmid2522013>{{cite journal | vauthors = DePoli P, Bacon-Baguley T, Kendra-Franczak S, Cederholm MT, Walz DA | title = Thrombospondin interaction with plasminogen. Evidence for binding to a specific region of the kringle structure of plasminogen | journal = Blood | volume = 73 | issue = 4 | pages = 976–982 | date = March 1989 | pmid = 2522013 | doi = 10.1182/blood.V73.4.976.976 | doi-access = free }}</ref> [[Alpha 2-antiplasmin]]<ref name=pmid158022>{{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><ref name=pmid2437112>{{cite journal | vauthors = Shieh BH, Travis J | title = The reactive site of human alpha 2-antiplasmin | journal = The Journal of Biological Chemistry | volume = 262 | issue = 13 | pages = 6055–6059 | date = May 1987 | pmid = 2437112 | doi = 10.1016/S0021-9258(18)45536-6 | doi-access = free }}</ref> and [[IGFBP3]].<ref name=pmid9688635>{{cite journal | vauthors = Campbell PG, Durham SK, Suwanichkul A, Hayes JD, Powell DR | title = Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3 | journal = The American Journal of Physiology | volume = 275 | issue = 2 | pages = E321–E331 | date = August 1998 | pmid = 9688635 | doi = 10.1152/ajpendo.1998.275.2.E321 }}</ref> Moreover, plasmin induces the generation of [[bradykinin]] in mice and humans through [[high-molecular-weight kininogen]] cleavage.<ref>{{cite journal | vauthors = Marcos-Contreras OA, Martinez de Lizarrondo S, Bardou I, Orset C, Pruvost M, Anfray A, Frigout Y, Hommet Y, Lebouvier L, Montaner J, Vivien D, Gauberti M | display-authors = 6 | title = Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism | journal = Blood | volume = 128 | issue = 20 | pages = 2423–2434 | date = November 2016 | pmid = 27531677 | doi = 10.1182/blood-2016-03-705384 | doi-access = free }}</ref>

== References ==
{{Reflist|33em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Shanmukhappa K, Mourya R, Sabla GE, Degen JL, Bezerra JA | title = Hepatic to pancreatic switch defines a role for hemostatic factors in cellular plasticity in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 29 | pages = 10182–10187 | date = July 2005 | pmid = 16006527 | pmc = 1177369 | doi = 10.1073/pnas.0501691102 | doi-access = free | bibcode = 2005PNAS..10210182S }}
* {{cite journal | vauthors = Anglés-Cano E, Rojas G | title = Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site | journal = Biological Chemistry | volume = 383 | issue = 1 | pages = 93–99 | date = January 2002 | pmid = 11928826 | doi = 10.1515/BC.2002.009 | s2cid = 29248198 }}
* {{cite journal | vauthors = Ranson M, Andronicos NM | title = Plasminogen binding and cancer: promises and pitfalls | journal = Frontiers in Bioscience | volume = 8 | issue = 6 | pages = s294–s304 | date = May 2003 | article-number = 1044 | pmid = 12700073 | doi = 10.2741/1044 }}
{{refend}}

== External links ==
*The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.233 S01.233] {{Webarchive|url=https://web.archive.org/web/20190913110221/http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=S01.233 |date=2019-09-13 }}
*{{MeshName|Plasmin}}

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[[Category:Acute-phase proteins]]
[[Category:Fibrinolytic system]]
[[Category:EC 3.4.21]]
[[Category:Extracellular matrix remodeling enzymes]]