Interactions of factor XIII with fibrin as substrate and cofactor.
Interactions of factor XIII with fibrin as substrate and cofactor.
复制标题
因子 XIII 与作为底物和辅因子的纤维蛋白的相互作用。
DOI：
10.1021/bi00117a017
复制
发表时间：
1992
期刊：
影响因子：
2.9
通讯作者：
Shafer,JA
中科院分区：
文献类型：
--
作者：
Hornyak,TJ;Shafer,JA
Department of Biological Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-0606 Received June 27, 1991; Revised Manuscript Received September 4, 1991 abstract: Factor XHIa (a2) is a homodimeric transglutaminase that is formed via limited a-thrombin-catalyzed proteolysis of the platelet (a2) or plasma (a2b2) factor XIII zymogen in a reaction that results in proteolytic removal of a 37-aminoacyl residue peptide from the N-terminus of the a chains and exposure of the active-site thiol group in the resulting a'chains of factor XHIa. In this study, we characterized interactions of factor XIII and factor XHIa with fibrin, a natural substrate for factor XHIa and a cofactor for the-thrombin-catalyzed activation of plasma factor XIII. The carbamylmethyl derivatives of the active-site thiol group of platelet factor XIII (CMa2) and factor XHIa (CMfl/) were prepared, and their interactions withfibrin were measured. The enzyme-like derivative (CMa/) which contained nicked a'chains bound more tightly to fibrin (Xd= 2.1 µ) than did CMo2 (ATd= 14 µ), the platelet zymogen-like derivative with intact a chains, but the binding of each was weaker than the binding of plasma factor XIII zymogen (a2b2) to fibrin (Xd=0.20 µ) under the same conditions. Saturationof fibrin with plasma factor XIII zymogen (a2b2) did not affect the binding of CMa/to fibrin, suggesting that the plasma factor XIII zymogen (a2b2) and the active-site-modifiedform of factor XHIa (CMa2') bind to separate, noninteracting sites of fibrin. In contrast to its promoting effect on the activation of plasma factor XIII, fibrin did not promote AP release from platelet factor XIII at concentrations of fibrin high enough to ensure significant binding of platelet factor XIII by fibrin, suggesting that the b chains in plasma factor XIII determine not only the affinity of a2b2 for fibrin but also the geometric disposition of a2b2 in the termolecular thrombin-fibrin-a2h2 complex that is involved in fibrin promotion of-thrombin-catalyzed activation of plasma factor XIII. An analysis of the effects of fibrinogen on the rate of release of b chains and concomitant exposure of the active-site thiol group in a-thrombin-cleaved plasma factor XIII (a2b2) yielded a value of 2.3 µ for the equilibrium constant for dissociation of the fibrinogen-a2b2 complex. The observation that the intact zymogen a2b2 did not antagonize the interaction of a2b2 with fibrinogen suggested that the proteolytic conversion of a2b2 to a2b2 results in altered interactions with fibrinogen.In the terminal stage of blood coagulation, the conversion of factor XIII to factor XHIa generates a transglutaminase activity which is an important determinant of the strength of the eventual fibrin clot and its resistance to fibrinolysis. Factor XIII is found in the body as plasma factor XIII, an a2b2 tetramer, and platelet factor XIII, an a2 dimer. Plasma factor XIII is cleaved by-thrombin to release activation peptide (AP) 1 from the N-termini of the a chains (Schwartz et al., 1973; Chung et al., 1974). In the presence of calcium ion, the b subunits dissociate from the cleaved zymogen to yield cat-alytically active factor XHIa (Chung et al., 1974; Lorand et al., 1974). Platelet factor XIII also yields the same active enzyme when cleaved by-thrombin in the presence of calcium ion. Details of the structures of the factor XIII a and b subunits have been reviewed (Ichinose et al., 1990). The activation pathways of plasma and platelet factor XIII are summarized in Scheme I according to previous findings (Schwartz et al., 1973; Chung et al., 1974; Lorand et al., 1974).
