Fibrin
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Template:Protbox header {{Protbox codes
|Symbol=FGA |AltSymbols= |Chromosome=4 |Locus=q28 |AApre=866 |AApro=--- |HGNCid= |Codes=Template:EntrezGene, Template:RefSeq, Template:UniProt, OMIM 134820
}} Template:Protbox finish Fibrin is a protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a haemostatic plug or clot (in conjunction with platelets) over a wound site.
Fibrin is made from its zymogen fibrinogen, a soluble plasma glycoprotein that is synthesised by the liver. Processes in the coagulation cascade activate the zymogen prothrombin to the serine protease thrombin, which is responsible for converting fibrinogen into fibrin. Fibrin is then cross linked by factor XIII to form a clot.
Fibrin generation
Fibrinogen is a 340-KD glycoprotein synthesised in the liver hepatocytes and megakaryocytes, which normally has a concentration between 1.5 - 4.0 g/L (normally measured using the Clauss method) in blood plasma. Dysfunction or disease of the liver can lead to a decrease in fibrinogen production or the production of abnormal fibrinogen molecules with reduced activity (dysfibrinogenaemia). Hereditary abnormalities of fibrinogen (the gene is carried on chromosome 4) are of both quantitative and qualitative in nature and include; afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia, and hypodysfibrinogenaemia. In its natural form, fibrinogen is useful in forming bridges between platelets, by binding to their GpIIb/IIIa surface membrane proteins; though fibrinogen's major use is as a precursor to fibrin.
Fibrinogen is a symmetrical dimer composed of 6 paired polypeptide chains. (alpha, beta, and gamma chains). On the alpha and beta chains, there is a small peptide sequence (called a fibrinopeptide). It is these small peptides that prevent fibrinogen spontaneously forming polymers with itself.
Fibrinogen, the principal protein of vertebrate blood clotting is an hexamer containing two sets of three different chains (α, β, and γ), linked to each other by disulfide bonds. The N-terminal sections of these three chains are evolutionary related and contain the cysteines that participate in the cross-linking of the chains. However, there is no similarity between the C-terminal part of the α chain and that of the β and γ chains. The C-terminal part of the β and γ chains forms a domain of about 270 amino-acid residues. As shown in the schematic representation this domain contains four conserved cysteines involved in two disulfide bonds.
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xxxxxxCxxxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxCxxxxxCxxxxxxxxxxxxx
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+------------+ +-----+
'C': conserved cysteine involved in a disulfide bond. '*': position of the pattern.
Such a domain has been recently found in other proteins which are listed below.
* Two sea cucumber fibrinogen-like proteins (FReP-A and FReP-B). These are proteins, of about 260 amino acids, which have a fibrinogen β/γ C- terminal domain. * In the C-terminus of Drosophila protein scabrous (gene sca). Scabrous is involved in the regulation of neurogenesis in Drosophila and may encode a lateral inhibitor of R8 cells differentiation. * In the C-terminus of mammalian Tenascin-X, an extracellular matrix protein that seems to be involved in cell adhesion. * In the C-terminus of mammalian prothrombinase.
The function of this domain is not yet known, but it has been suggested that it could be involved in protein-protein interactions. As a signature pattern for this domain, we selected the region around the fourth cysteine. (According to http://www.expasy.org/prosite/PDOC00445)
- FUNCTION: Fibrinogen has a double function: yielding monomers that polymerize into fibrin and acting as a cofactor in platelet aggregation.
- SUBUNIT: Heterohexamer; disulfide linked. Contains 2 sets of 3 nonidentical chains (alpha, beta and gamma). The 2 heterotrimers are in head to head conformation with the N-termini in a small central domain.
DOMAIN: A long coiled coil structure formed by 3 polypeptide chains connects the central nodule to the C-terminal domains (distal nodules). The long C-terminal ends of the alpha chains fold back, contributing a fourth strand to the coiled coil structure.
Conversion of fibrinogen to fibrin is triggered by thrombin, which cleaves fibrinopeptides A and B from alpha and beta chains, and thus exposes the N-terminal polymerization sites responsible for the formation of the soft clot. The soft clot is converted into the hard clot by factor XIIIA which catalyzes the epsilon-(gamma-glutamyl)lysine cross-linking between gamma chains (stronger) and between alpha chains (weaker) of different monomers. Accoring to: http://www.expasy.org/uniprot/FIBA_HUMAN http://www.expasy.org/uniprot/FIBB_HUMAN http://www.expasy.org/uniprot/FIBG_HUMAN
Following the activation of prothrombin to thrombin (Factor IIa). Thrombin cleaves fibrinopeptide A off the alpha chain and reveals a site in the E domain that can bind to the carboxy terminal end of the gamma chain. Beta chain cleavage occurs more slowly and contributes to the fibril and fiber associations of fibrinogen. These processes convert fibrinogen to fibrin.
The active molecules of fibrin stack up on each other, usually incorporating (by trapping) aggregrates of platelets and molecules of thrombin. The soluble fibrin molecules are later cross-linked (by factor XIII) with covalent bonds, to form a stable hemostatic plug, thus effectively stopping bleeding.
Fibrinogen as a marker of inflammation in horses
Fibrinogen is used by equine veterinary surgeons as a useful marker of non-specific inflammation. The normal range in horses is also 1.0 - 4.0 g/L but an elevation of fibrinogen above these levels suggests some degree of systemic inflammatory response. This response is due to fibrinogen's role as an acute phase protein.
See also
Template:Coagulationde:Fibrin fr:Fibrine nl:Fibrine ja:フィブリン pl:Fibryna pt:Fibrina fi:Fibrinogeeni sv:Fibrin