Structure and function of human fibrinogen inferred from dysfibrinogens

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 A alpha, B beta- and gamma-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 alpha-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 gamma-chain in the outer D domain of another molecule. By crystallographic analysis [3], the alpha-amino group of alpha Gly-1 is shown to be juxtaposed between the carboxyl group of gamma Asp-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 gamma-chain on the surface of the abutting two D domains [3]. Thereafter, carboxyl-terminal regions of the fibrin a-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.

Fibrinogen A Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

“…Recombinant fibrinogen lacking the Ca domain has also been shown to form clot in vitro that is less stiff and more susceptible to thrombolysis than clot formed in the presence of normal fibrinogen [31]. Further information about the role of the Ca domain has also been gained from studying hereditary dysfibrinogenaemias [32]. Dusart syndrome, caused by the substitution of Arg fibrinogen Aa for cysteine at position 554 within, is associated with increased a-a chain linkage, and hence enhanced lateral aggregation of fibrin protofibrils.…”

Fibrin Derived from Patients with Chronic Thromboembolic Pulmonary Hypertension Is Resistant to Lysis

“…Although these experiments are the first to systematically study fibrinolytic resistance in a series of patients with CTEPH, numerous genetic variants of human fibrinogen have been implicated in thrombotic diseases (20). Notably, fibrinogen Bellingham, which involves a ␥ 275 Arg → Cys substitution, was reported in a patient with CTEPH and conferred a relative resistance to plasmin-mediated fibrinolysis (21).…”

Characterization of myofibroblasts in chronic thromboembolic pulmonary hypertension

“…These molecular alternations are paralleled by a resistance to thrombolysis [11]. However, this explanation is not sufficient because numerous genetic variants of human fibrinogen have been implicated in thrombotic diseases [14] and the resistance could be ascribed to, not only fibrinogen genetic polymorphisms, but also variances in posttranslational modifications. An alternative mechanism may be in situ thrombosis in the lung initiated by a primary arteriopathy and/or endothelial dysfunction.…”