Definition
Nonsubstrate interaction of thrombin with fibrinogen promotes sequential cleavage of fibrinopeptides A and B (FPA and FPB, respectively) from the latter, resulting in its conversion into fibrin1.
Related peptides
The three forms of FPA (AP, A, AY) and two forms of FPB (B, des Arg B) have be identified and quantified in biological samples. Amino acid substitutions in these forms are associated with a number of congenital fibrinogen abnormalities2.
Discovery
In 1951, Lorand et al., reported cleavage of fibrinopeptides from fibrinogen during fibrin clot formation3.
Structural Characteristics
Fibrinogen is cleaved by thrombin at Arg16-Gly17 of the Aa chain and at Arg14-Gly15 of them Bß chain, releasing fibrinopeptides A and B, respectively, and exposing new amino terminal ends of the a and ß - chains, and these are involved in polymerization. FPB cleavage and exposure of the p 15-42 region of the fibrin molecule by thrombin is necessary to stimulate spreading of adherent endothelial cells4. The amino acid sequences of human FPA and FPB are reported to be:H - Ala - Asp - Ser - Gly - Glu - Gly - Asp - Phe - Leu - Ala - Glu - Gly - Gly - Gly - Val - Arg – OH, and Pyr - Gly - Val - Asn - Asp - Asn - Glu - Glu - Gly - Phe - Phe - Ser - Ala - Arg - OH, respectively.
Mode of Action
To convert soluble fibrinogen to insoluble fibrin, thrombin cleaves fibrinopeptide A (FpA, A 1-16) to expose the "A" polymerization site. This "A" site noncovalently interacts with the "a" polymerization site in the C domain of another fibrinogen molecule. This A: a interaction results in the spontaneous formation of half-staggered, double-stranded protofibrils. As these protofibrils grow in length, thrombin cleaves FPB (FpB, B 1-14), which exposes the "B" site and dissociates the C domains from the central E nodule. The release of FpB results in an enhanced rate of lateral aggregation of protofibrils to form thick fibers. Lateral aggregation is supported by multiple interactions, including: a specific, noncovalent interaction between the "B" site and the "b" polymerization site in the C domain of another molecule, intermolecular interactions between C domains of different fibrin molecules, and interactions between 2 C domains of different protofibrils, specifically residues 330 to 375. The end result of thrombin-catalyzed polymerization is the formation of a complex branching network of insoluble fibers5.
Functions
Thrombin cleavage of fibrinogen into FPA and FPB is essential for fibrin clot formation. FPA and FPB, cleavage products of the Aa and Bß chains, respectively, have both been reported to cause vasoconstriction6, and FPB is a chemoattractant for neutrophils and fibroblasts at certain concentrations7. Potentiation of fibroblast proliferation by FPA and FPB has also been suggested7, and both peptides have been found to possess mitogenic activity8.
References
1. Pechik I, Yakovlev S, Mosesson MW, Gilliland GL, Medved L (2006). Structural Basis for Sequential Cleavage of Fibrinopeptides upon Fibrin Assembly. Biochemistry, 45(11): 3588–3597.
2. Southan C, Thompson E, Lane DA (1987). Direct analysis of plasma fibrinogen-derived fibrinopeptides by high-performance liquid chromatography: investigation of nine congenital fibrinogen abnormalities. Br journal of Haematology, 65(4):469-473.
3. Lorand L (1951). 'Fibrino-Peptide'; New Aspects of the Fibrinogen–Fibrin Transformation. Nature, 167(4259):992-993.
4. Sporn LA, Bunce LA, Francis CW (1995). Cell proliferation on fibrin: modulation by fibrinopeptide cleavage. Blood, 86(5):1802-1810.
5. Moen JL, Gorkun OV, Weisel JW, Lord ST(2003). Recombinant BßArg14His fibrinogen implies participation of N-terminus of Bßchain in desA fibrin polymerization. Blood, 102(7): 2466-2471.
6. Bayley T, Clements JA, Osbahr AJ (1967). Pulmonary and circulatory effects of fibrinopeptides. Circ Res., 21 (4):469-485.
7. Senior RM, Skogen WF, Griffin GL, Wilner GD(1986). Effects of fibrinogen derivatives upon the inflammatory response. Studies with human fibrinopeptide B. J Clin Invest, 77(3):1014-1019.
8. Gray AJ, Reeves JT, Harrison NK, Winlove P, Laurent GJ (1990). Growth factors for human fibroblasts in the solute remaining after clot formation. J Cell Sci., 96: 271-274.