Summary: Fibrinogen alpha/beta chain family
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Fibrinogen Edit Wikipedia article
||This article may be in need of reorganization to comply with Wikipedia's layout guidelines. (February 2012)|
|fibrinogen gamma chain|
|Locus||Chr. 4 q28|
|fibrinogen beta chain|
|Locus||Chr. 4 q28|
|fibrinogen gamma chain|
|Locus||Chr. 4 q28|
|Fibrinogen alpha/beta chain family|
crystal structure of native chicken fibrinogen with two different bound ligands
|Fibrinogen alpha C domain|
|Fibrinogen beta and gamma chains, C-terminal globular domain|
crystal structure of native chicken fibrinogen with two different bound ligands
Fibrinogen (factor I) is a soluble, 340 kDa plasma glycoprotein, that is converted by thrombin into fibrin during blood clot formation. Fibrinogen is synthesized in the liver by the hepatocytes. The concentration of fibrinogen in the blood plasma is 200–400 mg/dL (normally measured using the Clauss method).
During normal blood coagulation, a coagulation cascade activates the zymogen prothrombin by converting it into the serine protease thrombin. Thrombin then converts the soluble fibrinogen into insoluble fibrin strands. These strands are then cross-linked by factor XIII to form a blood clot. FXIIIa stabilizes fibrin further by incorporation of the fibrinolysis inhibitors alpha-2-antiplasmin and TAFI (thrombin activatable fibrinolysis inhibitor, procarboxypeptidase B), and binding to several adhesive proteins of various cells. Both the activation of Factor XIII by thrombin and plasminogen activator (t-PA) are catalyzed by fibrin. Fibrin specifically binds the activated coagulation factors factor Xa and thrombin and entraps them in the network of fibers, thus functioning as a temporary inhibitor of these enzymes, which stay active and can be released during fibrinolysis. Recent research has shown that fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis.
Fibrinogen, the principal protein of vertebrate blood clotting, is a hexamer, containing two sets of three different chains (α, β, and γ), linked to each other bydisulfide bonds. The N-terminal sections of these three chains contain the cysteines that participate in the cross-linking of the chains. TheC-terminal parts of the α, β and γ chains contain a domain of about 225 amino-acid residues, which can function as a molecular recognition unit. In fibrinogen as well as in angiopoietin, this domain is implicated in protein-protein interactions. In lectins, such as mammalianficolins and invertebrate tachylectin 5A, the fibrinogen C-terminal domain binds carbohydrates. On the fibrinogen α and β chains, there is a smallpeptide sequence (called a fibrinopeptide). These small peptides are what prevent fibrinogen from spontaneously forming polymers with itself.
The conversion of fibrinogen to fibrin occurs in several steps. First, thrombin cleaves the N-terminus of the fibrinogen alpha and beta chains to fibrinopeptide A and B respectively. The resulting fibrin monomers polymerize end to end to from protofibrils, which in turn associate laterally to form fibrin fibers. In a final step, the fibrin fibers associate to form the fibrin gel.
Congenital fibrinogen deficiency (afibrinogenemia) or disturbed function of fibrinogen has been described in a few cases.
It can lead to either bleeding or thromboembolic complications, or is clinically without pathological findings. More common are acquired deficiency stages that can be detected by laboratory tests in blood plasma or in whole blood by means of thrombelastometry. Acquired deficiency is found after hemodilution, blood losses and/or consumption such as in trauma patients, during some phases of disseminated intravascular coagulation (DIC), and also in sepsis. In patients with fibrinogen deficiency, the correction of bleeding is possible by infusion of fresh frozen plasma (FFP), cryoprecipitate (a fibrinogen-rich plasma fraction) or by fibrinogen concentrates. There is increasing evidence that correction of fibrinogen deficiency or fibrinogen polymerization disorders is very important in patients with bleeding.
Fibrinogen levels can be measured in venous blood. Normal levels are about 1.5-3 g/L, depending on the method used. In typical circumstances, fibrinogen is measured in citrated plasma samples in the laboratory, however the analysis of whole-blood samples by use of thrombelastometry (platelet function is inhibited with cytochalasin D) is also possible. Higher levels are, amongst others, associated with cardiovascular disease (>3.43 g/L). It may be elevated in any form of inflammation, as it is an acute-phase protein; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease. Fibrinogen levels increase in pregnancy to an average of 4.5 g/l, compared to an average of 3 g/l in non-pregnant people.
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 aPTT), in the context of acute critical illness such as sepsis or trauma. Besides low fibrinogen level, fibrin polymerization disorders that can be induced by several factors, including plasma expanders, can also lead to severe bleeding problems. Fibrin polymerization disorders can be detected by viscoelastic methods such as thrombelastometry.
- PDB 1FZC; Everse SJ, Spraggon G, Veerapandian L, Riley M, Doolittle RF (June 1998). "Crystal structure of fragment double-D from human fibrin with two different bound ligands". Biochemistry 37 (24): 8637–42. doi:10.1021/bi9804129. PMID 9628725.
- Muszbek L, Bagoly Z, Bereczky Z, Katona E (July 2008). "The involvement of blood coagulation factor XIII in fibrinolysis and thrombosis". Cardiovascular & Hematological Agents in Medicinal Chemistry 6 (3): 190–205. doi:10.2174/187152508784871990. PMID 18673233.
- Kaiser B (2003). "DX-9065a, a direct inhibitor of factor Xa". Cardiovascular Drug Reviews 21 (2): 91–104. doi:10.1111/j.1527-3466.2003.tb00108.x. PMID 12847561.
- Gilliam BE; Reed, Melinda R; Chauhan, Anil K; Dehlendorf, Amanda B; Moore, Terry L (2011). "Evidence of Fibrinogen as a Target of Citrullination in IgM Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis". Pediatric Rheumatology 9 (8): xx–xx. doi:10.1186/1546-0096-9-8. ISSN 1546-0096. PMC 3071779. PMID 21439056.
- PDOC00445 Fibrinogen C-terminal domain in PROSITE
- Blombäck B, Hessel B, Hogg D, Therkildsen L (October 1978). "A two-step fibrinogen--fibrin transition in blood coagulation". Nature 275 (5680): 501–5. doi:10.1038/275501a0. PMID 692730.
- Hermans J, McDonagh J (January 1982). "Fibrin: structure and interactions". Semin. Thromb. Hemost. 8 (1): 11–24. doi:10.1055/s-2007-1005039. PMID 7036348.
- Lorand L, Credo RB; John W. Fenton, Kenneth G. Mann (1977). "hrombin and fibrin stabilization". In Mann KG, Lundblad RL, Fenton J. Chemistry and Biology of Thrombin. Ann Arbor, Mich: Ann Arbor Science Publishers. pp. 311–323. ISBN 0-250-40160-6.
- Acharya SS, Dimichele DM (November 2008). "Rare inherited disorders of fibrinogen". Haemophilia : the Official Journal of the World Federation of Hemophilia 14 (6): 1151–8. doi:10.1111/j.1365-2516.2008.01831.x. PMID 19141154.
- Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA (March 2009). "The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia". Anesthesia and Analgesia 108 (3): 751–8. doi:10.1213/ane.0b013e3181966675. PMID 19224779.
- Fries D, Innerhofer P, Schobersberger W (April 2009). "Time for changing coagulation management in trauma-related massive bleeding". Current Opinion in Anaesthesiology 22 (2): 267–74. doi:10.1097/ACO.0b013e32832678d9. PMID 19390253.
- Page RC, Schroeder HE (March 1976). "Pathogenesis of inflammatory periodontal disease. A summary of current work". Lab. Invest. 34 (3): 235–49. PMID 765622.
- Salvi, Vinita (2003). Medical and Surgical Diagnostic Disorders in Pregnancy. Jaypee Brothers Publishers. p. 5. ISBN 978-81-8061-090-5.
- Jennifer McDowall/Interpro: Protein Of The Month: Fibrinogen.
- D'Eustachio/reactome: fibrinogen → fibrin monomer + 2 fibrinopeptide A + 2 fibrinopeptide B
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Fibrinogen alpha/beta chain family Provide feedback
Fibrinogen is a protein involved in platelet aggregation and is essential for the coagulation of blood. This domain forms part of the central coiled coiled region of the protein which is formed from two sets of three non-identical chains (alpha, beta and gamma).
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR012290
Fibrinogen plays key roles in both blood clotting and platelet aggregation. During blood clot formation, the conversion of soluble fibrinogen to insoluble fibrin is triggered by thrombin, resulting in the polymerisation of fibrin, which forms a soft clot; this is then converted to a hard clot by factor XIIIA, which cross-links fibrin molecules. Platelet aggregation involves the binding of the platelet protein receptor integrin alpha(IIb)-beta(3) to the C-terminal D domain of fibrinogen [PUBMED:12799374]. In addition to platelet aggregation, platelet-fibrinogen interaction mediates both adhesion and fibrin clot retraction.
Fibrinogen occurs as a dimer, where each monomer is composed of three non-identical chains, alpha, beta and gamma, linked together by several disulphide bonds [PUBMED:11460466]. The N-terminals of all six chains come together to form the centre of the molecule (E domain), from which the monomers extend in opposite directions as coiled coils, followed by C-terminal globular domains (D domains). Therefore, the domain composition is: D-coil-E-coil-D. At each end, the C-terminal of the alpha chain extends beyond the D domain as a protuberance that is important for cross-linking the molecule.
During clot formation, the N-terminal fragments of the alpha and beta chains (within the E domain) in fibrinogen are cleaved by thrombin, releasing fibrinopeptides A and B, respectively, and producing fibrin. This cleavage results in the exposure of four binding sites on the E domain, each of which can bind to a D domain from different fibrin molecules. The binding of fibrin molecules produces a polymer consisting of a lattice network of fibrins that form a long, branching, flexible fibre [PUBMED:11593005, PUBMED:15837518]. Fibrin fibres interact with platelets to increase the size of the clot, as well as with several different proteins and cells, thereby promoting the inflammatory response and concentrating the cells required for wound repair at the site of damage.
This entry represents the coiled-coil domain and part of the N-terminal E domain found in all three fibrinogen polypeptides, namely the alpha, beta and gamma chains.
More information about these proteins can be found at Protein of the Month: Fibrinogen [PUBMED:].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||fibrinogen complex (GO:0005577)|
|Molecular function||protein binding, bridging (GO:0030674)|
|receptor binding (GO:0005102)|
|Biological process||protein polymerization (GO:0051258)|
|signal transduction (GO:0007165)|
|platelet activation (GO:0030168)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||pdb_1m1j & pdb_2a45|
|Number in seed:||20|
|Number in full:||256|
|Average length of the domain:||130.80 aa|
|Average identity of full alignment:||29 %|
|Average coverage of the sequence by the domain:||29.67 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||5|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Fib_alpha domain has been found. There are 240 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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