Fibrin: Difference between revisions
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Fibrinogen (also called factor I) is a 340 k[[Da]] glycoprotein synthesised in the liver [[hepatocytes]] and [[megakaryocytes]], which [[reference range|normally]] has a concentration between 1.5 - 4.0 g/L (normally measured using the [[Clauss]] method) in blood plasma. 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 (also called factor I) is a 340 k[[Da]] glycoprotein synthesised in the liver [[hepatocytes]] and [[megakaryocytes]], which [[reference range|normally]] has a concentration between 1.5 - 4.0 g/L (normally measured using the [[Clauss]] method) in blood plasma. 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. |
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Fibrinogen is a symmetrical [[dimer]] composed of 6 paired |
Fibrinogen is a symmetrical [[dimer]] composed of 6 paired hi mompolypeptide chains. (alpha, beta, and gamma chains). On thehimom 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. |
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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 [[Cysteine|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. |
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 [[Cysteine|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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Revision as of 21:08, 22 February 2007
| fibrinogen alpha chain | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | FGA | ||||||
| NCBI gene | 2243 | ||||||
| HGNC | 3661 | ||||||
| OMIM | 134820 | ||||||
| RefSeq | NM_000508 | ||||||
| UniProt | P02671 | ||||||
| Other data | |||||||
| Locus | Chr. 4 q28 | ||||||
| |||||||
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 hemostatic 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.
Physiology
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Fibrinogen (also called factor I) is a 340 kDa 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. 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 hi mompolypeptide chains. (alpha, beta, and gamma chains). On thehimom 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.
*****
xxxxxxCxxxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxCxxxxxCxxxxxxxxxxxxx
| | | |
+------------+ +-----+
'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. According 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.
Role in disease
Excessive generation of fibrin due to activation of the coagulation cascade leads to thrombosis, while ineffective generation predisposes to hemorrhage.
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.
Diagnostic use
Fibrinogen levels can be measured in venous blood. Normal levels are about 150-300mg/dL. Higher levels are, amongst others, associated with cardiovascular disease (>460mg/dL). It may be elevated in any form of inflammation, as it is an acute phase protein.
It is used in veterinary medicine as an inflammatory marker: in horses a level above the normal range of 1.0-4.0 g/L suggests some degree of systemic inflammatory response.
Low levels of fibrinogen can indicate a systemic activation of the clotting system, with consumption of clotting factors faster than synthesis. This excessive clotting factor consumption condition is known as Disseminated Intravascular Coagulation or "DIC." DIC can be difficult to diagnose, but a strong clue is low fibrinogen levels in the setting of prolonged clotting times (PT or PTT), in the context of acute critical illness such as sepsis or trauma.