Update on Hemostasis and Thrombosis

International Journal of Hematology

, Volume 76, Issue 1, pp 352-360

Structure and function of human fibrinogen inferred from dysfibrinogens

  • Michio MatsudaAffiliated withDivision of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical SchoolOgata Institute for Medical and Chemical Research
  • , Teruko SugoAffiliated withDivision of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School

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Abstract

Fibrinogen is a 340-kDa plasma protein that is composed of two identical molecular halves, each consisting of three non-identical subunit polypeptides designated as Aa, Bβ- and λ-chains held together by multiple disulfide bonds. Fibrinogen has a trinodular structure, i.e., one central E domain comprizing the amino-terminal regions of paired individual three polypeptides, and two identical outer D domains. These three nodules are linked by two coiled-coil regions [1,2]. After activation with thrombin, a tripeptide segment consisting of Gly-Pro-Arg is exposed at the amino-terminus of each α-chain residing at the center of the E domain and combines with its complementary binding site, called the ‘a’ site, residing in the carboxyl-terminal region of the γ-chain in the outer D domain of another molecule. By crystallographic analysis [3], the α-amino group of αGly-1 is shown to be juxtaposed between the carboxyl group of γAsp-364 and the carboxyamide of Gln-329 in the ‘a’ site. Half molecule-staggered, double-stranded fibrin protofibrils are thus formed [4,5]. 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 [3]. Thereafter, carboxyl-terminal regions of the fibrin α-chains are thought to be untethered and interact with those of other protofibrils leading to the formation of thick fibrin bundles and interwoven networks after appropriate branching [6–9]. Although many enigmas still remain regarding the mechanisms of these molecular interactions, fibrin assembly proceeds in a highly ordered fashion. In my talk, I would like to discuss these molecular interactions of fibrinogen and fibrin based on the up-date data provided by analyses of normal as well as hereditary dysfibrinogens, particularly in the latter by introducing representative molecules at each step of fibrin clot formation.