Structure and function of fibrinogen inferred from hereditary dysfibrinogens

Abstract

Fibrinogen is a 340-kDa plasma protein that participates in the final step of blood coagulation. Fibrinogen is composed of two identical molecular halves, each molecular half consisting of three non-identical Aα-, Bβ- and γ-chain subunits held together by multiple disulfide bonds. Fibrinogen is shown to have a trinodular structure, namely: one central nodule – the E domain – and two identical outer nodules – the D-domains – linked by two coiled-coil regions. After activation with thrombin, a pair of binding sites comprising Gly-Pro-Arg is exposed in the central domain, and combines with the complementary binding site ‘a’ in the outer D domain of another molecules. By crystallographic analysis, the α-amino group of Gly-1 is shown to be juxtaposed between Asp-364 and Asp-330 and the guanidino group of Arg-3 between the carboxyl group of Asp-364 and Gln-329 comprising the ‘a’ site. The half molecule-staggered, double-stranded protofibrils are thus formed. Upon abutment of two adjacent D domains on the same strand, D-D self association takes place involving Arg-275, Tyr-280 and Ser-300 of the γ-chain on the surface of the abutting two D domains. Thereafter, carboxy-terminal regions of the α-chains are untethered and interact with those of another protofibrils leading to the formation of thick fibrin bundles and networks. Although many enigmas still remain with regard to the exact mechanisms of these molecular interactions, they proceed in a highly ordered fashion.

In this review, these molecular interactions of fibrinogen and fibrin are discussed by introducing representative abnormal fibrinogen molecules at each step of fibrin clot formation.