View source for Factor XIII

{{Short description|Class of enzymes}}
{{Infobox protein
| Name = [[F13A1|coagulation factor XIII,<br />A1 polypeptide]]
| caption = Inactive A1 peptide homodimer with all of the domains and main catalytic residues shown with different colors.
| image = Human factor XIII 1EVU.png
| width = 
| HGNCid = 3531
| Symbol = [[F13A1]]
| AltSymbols = F13A
| EntrezGene = 2162
| OMIM = 134570
| RefSeq = NM_000129
| UniProt = P00488
| PDB = 
| ECnumber = 2.3.2.13
| Chromosome = 6
| Arm = p
| Band = 24
| LocusSupplementaryData = .2-p23
}}
{{Infobox protein
| Name = [[F13B|coagulation factor XIII,<br />B polypeptide]]
| caption = 
| image = 
| width = 
| HGNCid = 3534
| Symbol = [[F13B]]
| AltSymbols = 
| EntrezGene = 2165
| OMIM = 134580
| RefSeq = NM_001994
| UniProt = P05160
| PDB = 
| ECnumber = 
| Chromosome = 1
| Arm = q
| Band = 31
| LocusSupplementaryData = -q32.1
}}

'''Factor XIII''', or '''fibrin stabilizing factor''', is a [[plasma protein]] and [[zymogen]]. It is activated by [[thrombin]] to [[factor XIIIa]] which [[crosslink]]s [[fibrin]] in [[coagulation]]. Deficiency of XIII worsens clot stability and increases bleeding tendency.<ref name=a>{{cite journal | vauthors = Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É | s2cid = 24703788 | title = Factor XIII: a coagulation factor with multiple plasmatic and cellular functions | journal = Physiological Reviews | volume = 91 | issue = 3 | pages = 931–72 | date = July 2011 | pmid = 21742792 | doi = 10.1152/physrev.00016.2010 }}</ref>

Human XIII is a [[heterotetramer]]. It consists of 2 enzymatic [[F13A1|A peptides]] and 2 non-enzymatic [[F13B|B peptides]]. XIIIa is a [[Protein dimer|dimer]] of activated A peptides.<ref name=a/>

== Function ==
Within blood, [[thrombin]]s cleave [[fibrinogen]]s to fibrins during coagulation and a fibrin-based blood clot forms. Factor XIII is a [[transglutaminase]] that circulates in human blood as a [[Tetrameric protein|heterotetramer]] of two A and two B subunits. Factor XIII binds to the clot via their B units. In the presence of fibrins, thrombin efficiently cleaves the [[Arginine|R]]37–[[Glycine|G]]38 [[peptide bond]] of each A unit within a XIII tetramer. A units release their [[N-terminal]] activation [[peptide]]s.<ref name=a/>

Both of the non-[[covalently]] bound B units are now able to dissociate from the tetramer with the help of [[calcium]] ions (Ca<sup>2+</sup>) in the blood; these ions also activate the remaining dimer of two A units via a conformational change.<ref name=a/>

Factor XIIIa (dimer of two active A units) [[Cross-link|crosslinks]] fibrins within the clot by forming [[isopeptide bond]]s between various [[glutamine]]s and [[lysine]]s of the fibrins. These bonds make the clot physically more durable  and protect it from premature enzymatic degradation ([[fibrinolysis]]).<ref name=a/>

In humans, [[plasmin]], [[antithrombin]] and [[TFPI]] are the most relevant proteolytic inhibitors of the active factor XIIIa. [[α2-macroglobulin]] is a significant non-proteolytic inhibitor.<ref name=a/>
<gallery mode="packed" heights="300px">
Factor XIII activation via thrombin.svg|Activation peptides (pink) of A units are removed by thrombin (IIa) in the presence of fibrin. B units (gray) are released with the help of calcium and A unit dimer is activated (XIIIa forms).
Stabilisation de la fibrine par le factor XIII.png|XIIIa crosslinks fibrin (simplified picture)
</gallery>

==Genetics==
Human factor XIII consist of A and B subunits. A subunit [[gene]] is ''[[F13A1]]''. It is on [[chromosome 6]] at the position 6p24–25. It spans over 160 [[Base pair|kbp]], has 14 [[intron]]s and 15 [[exon]]s. Its [[mRNA]] is 3.9 kbp. It has a [[5' UTR]] of 84 bp and a [[3' UTR]] of 1.6 kbp. ''F13A1'' exon(s)<ref name=a/>

*1 code 5' UTR
*2 code activation peptide
*2–4 code [[β-sandwich]]
*4–12 code [[catalytic domain]]
*12–13 code [[β-barrel]] 1
*13–15 code β-barrel 2

B subunit gene is ''[[F13B]]''. It is on [[chromosome 1]] at the position 1q31–32.1. It spans 28 kbp, has 11 introns and 12 exons. Its mRNA is 2.2 kbp. Exon 1 codes 5' UTR. Exons 2–12 code the 10 different [[sushi domain]]s.<ref name=a/>

== Structure ==
Factor XIII of human blood is a [[heterotetramer]] of two A and two B linear polypeptides or "units". A units are potentially catalytic; B units are not. A units form a [[Protein dimer|dimeric]] center. Non-[[covalently]] bound B units form a ring-like structure around the center. B units are removed when XIII is activated to XIIIa. Dimers containing only A units also occur within cells such as [[platelet]]s. Large quantities of singular B units (monomers) also occur within blood. These dimers and monomers are not known to participate in coagulation, whereas the tetramers do.<ref name=a/>

A units have a mass of about 83 [[kDa]], 731 [[amino acid]] residues, 5 [[protein domain]]s (listed from the [[N-terminal]] to [[C-terminal]], residue numbers are in brackets):<ref name=a/>

*activation peptide (1–37) 
*[[β-sandwich]] (38–184) 
*[[catalytic domain]] (185–515), in which the residues [[Cysteine|C]]314, [[Histidine|H]]373, [[Aspartic acid|D]]396 and [[Tryptophan|W]]279 partake in catalysis 
*[[β-barrel]] 1 (516–628) 
*β-barrel 2 (629–731)

B units are [[glycoprotein]]s. Each has a mass of about 80 kDa (8.5% of the mass is from [[carbohydrate]]s), 641 residues and 10 [[sushi domain]]s. Each domain has about 60 residues and 2 internal [[disulfide bonds]].<ref name=a/>

==Physiology==
A subunits of human factor XIII are made primarily by [[platelet]]s and other cells of [[bone marrow]] origin. B subunits are secreted into blood by [[hepatocyte]]s. A and B units combine within blood to form heterotetramers of two A units and two B units. [[Blood plasma]] concentration of the heterotetramers is 14–48&nbsp;mg/L and [[half-life]] is 9–14&nbsp;days.<ref name=a/>

A clot that has not been stabilized by FXIIIa is soluble in 5&nbsp;mol/L [[urea]], while a stabilized clot is resistant to this phenomenon.<ref name=Laki/>

==Factor XIII deficiency==
[[Factor XIII deficiency]], while generally rare, does occur, with [[Iran]] having the highest global incidence of the disorder with 473 cases. The city of [[Khash, Iran|Khash]], located in [[Sistan]] and [[Balochistan]] provinces, has the highest incidence in Iran, with a high rate of [[consanguineous]] marriage.<ref>{{cite journal|display-authors=etal|vauthors=Dorgalaleh A, Naderi M, Hosseini MS, Alizadeh S, Hosseini S, Tabibian S|date=2015|title=Factor XIII Deficiency in Iran: A Comprehensive Review of the Literature. Seminars in thrombosis and hemostasis|volume=41|issue=3 |pages=323–29}}</ref>

==Diagnostic use==
Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for [[monocyte]]s and [[macrophage]]s, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells.<ref name=Muszbek/>

==Discovery==
Factor XIII Deficiency is also known as Laki–Lorand factor, after [[Kalman Laki]] and [[Laszlo Lorand]], the scientists who first proposed its existence in 1948.<ref name="Laki">{{cite journal | vauthors = Laki K, Lóránd L | title = On the Solubility of Fibrin Clots | journal = Science | volume = 108 | issue = 2802 | pages = 280 | date = September 1948 | pmid = 17842715 | doi = 10.1126/science.108.2802.280 | bibcode = 1948Sci...108..280L }}</ref> A 2005 conference recommended standardization of nomenclature.<ref name="Muszbek">{{cite journal | vauthors = Muszbek L, Ariëns RA, Ichinose A | title = Factor XIII: recommended terms and abbreviations | journal = Journal of Thrombosis and Haemostasis | volume = 5 | issue = 1 | pages = 181–83 | date = January 2007 | pmid = 16938124 | doi = 10.1111/j.1538-7836.2006.02182.x | s2cid = 20424049 | doi-access = free }}</ref>

== See also ==
* [[Catridecacog]]
* [[Coagulation]]
* [[D-dimer]]
* [[Factor XIII deficiency]]

== References ==
{{Reflist}}

== External links ==
*[http://www.hemophilia.org/bdi/bdi_types11.htm Factor XIII deficiency at hemophilia.org]
*{{eMedicine|med|3491}}

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{{Acyltransferases}}
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[[Category:Coagulation system]]
[[Category:EC 2.3.2]]
[[Category:Zymogens]]