{PDOC00445} {PS00514; FIBRINOGEN_C_1} {PS51406; FIBRINOGEN_C_2} {BEGIN} ****************************************************** * Fibrinogen C-terminal domain signature and profile * ****************************************************** Fibrinogen, the principal protein of vertebrate blood clotting is a hexamer containing two sets of three different chains (alpha, beta, and gamma), linked to each other by disulfide bonds [1,2]. The N-terminal sections of these three chains contain the cysteines that participate in the cross-linking of the chains. The C-terminal parts of the alpha, beta and gamma chains contain a domain of about 225 amino-acid residues, which can function as a molecular recognition unit [2-6]. In fibrinogen as well as in angiopoietin this domain is implicated in protein-protein interactions. In lectins, such as mammalian ficolins and invertebrate tachylectin 5A, the fibrinogen C-terminal domain binds carbohydrates. As shown in the schematic representation this domain contains four conserved cysteines involved in two disulfide bonds. ***** xxxxxxCxxxxxxxxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxCxxxxxCxxxxxxxxxxxxx | | | | +------------+ +-----+ A B P 'C': conserved cysteine involved in a disulfide bond. '*': position of the pattern. 'A,B,P': regions within the domain The 3D structure of the fibrinogen C-terminal domain (see ) shows a fold composed of three separate regions [2,5-7]. The N-terminal region, also termed A domain, forms a helix and a beta-sheet held together by the first disulfide bond. The second region, or B domain, is the largest. The third region, also termed P domain, forms long extended coil regions and contains the C-terminal disulfide bond. This P region is the most divergent and contains most ligand binding sites and in some cases residues implicated in calcium binding. Some proteins known to contain a fibrinogen C-terminal domain: - Vertebrate fibrinogen alpha, beta and gamma chains. - Mammalian tenascin-X, an extracellular matrix protein that mediates interactions between cells and the extracellular matrix and accelerates collagen fibril formation. The C-terminal fibrinogen domain binds with fibrillar proteins in the extracellular matrix. - Vertebrate angiopoietin proteins, which contain a C-terminal fibrinogen domain that interacts with tyrosine-protein kinase receptor TIE2. - Mammalian prothrombinase or fibroleukin. - Sea cucumber fibrinogen-like protein A. - Fruit fly protein scabrous (gene sca). Scabrous is involved in the regulation of neurogenesis in Drosophila and may encode a lateral inhibitor of R8 cells differentiation. - Horseshoe crab techylectin-5A, a nonself-recognizing lectin with a fibrinogen C-terminal domain that recognizes carbohydrates. - Mammalian ficolins, with a collagen-like domain and a C-terminal fibrinogen domain that contains potential calcium-binding sites and can interact with GlcNAc. As a signature pattern for this domain, we selected the region around the fourth cysteine. We also developed a profile that covers the entire fibrinogen C-terminal domain. -Consensus pattern: W-W-[LIVMFYW]-x(2)-C-x(2)-[GSA]-x(2)-N-G [C is involved in a disulfide bond] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Note: In contactin-associated proteins (Cntnap/Caspr) and intelectins (Itln) only the N-terminal 'A' region of the fibrinogen C-terminal domain is well conserved and detected. -Expert(s) to contact by email: Doolittle R.F.; rdoolittle@ucsd.edu -Last update: September 2008 / Text revised; profile added. [ 1] Doolittle R.F. "Fibrinogen and fibrin." Annu. Rev. Biochem. 53:195-229(1984). PubMed=6383194; DOI=10.1146/annurev.bi.53.070184.001211 [ 2] Spraggon G., Everse S.J., Doolittle R.F. "Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin." Nature 389:455-462(1997). PubMed=9333233; DOI=10.1038/38947 [ 3] Xu X., Doolittle R.F. "Presence of a vertebrate fibrinogen-like sequence in an echinoderm." Proc. Natl. Acad. Sci. U.S.A. 87:2097-2101(1990). PubMed=2315305 [ 4] Baker N.E., Mlodzik M., Rubin G.M. "Spacing differentiation in the developing Drosophila eye: a fibrinogen-related lateral inhibitor encoded by scabrous." Science 250:1370-1377(1990). PubMed=2175046 [ 5] Kairies N., Beisel H.G., Fuentes-Prior P., Tsuda R., Muta T., Iwanaga S., Bode W., Huber R., Kawabata S. "The 2.0-A crystal structure of tachylectin 5A provides evidence for the common origin of the innate immunity and the blood coagulation systems." Proc. Natl. Acad. Sci. U.S.A. 98:13519-13524(2001). PubMed=11707569; DOI=10.1073/pnas.201523798 [ 6] Barton W.A., Tzvetkova-Robev D., Miranda E.P., Kolev M.V., Rajashankar K.R., Himanen J.P., Nikolov D.B. "Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex." Nat. Struct. Mol. Biol. 13:524-532(2006). PubMed=16732286; DOI=10.1038/nsmb1101 [ 7] Kostelansky M.S., Lounes K.C., Ping L.F., Dickerson S.K., Gorkun O.V., Lord S.T. "Calcium-binding site beta 2, adjacent to the 'b' polymerization site, modulates lateral aggregation of protofibrils during fibrin polymerization." Biochemistry 43:2475-2483(2004). PubMed=14992585; DOI=10.1021/bi0359978 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}