Structure and function of human fibrinogen inferred from dysfibrinogens
Structure and function of human fibrinogen inferred from dysfibrinogens
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DOI：
10.1007/bf03165284
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发表时间：
2002-08-01
影响因子：
2.1
通讯作者：
Sugo, T
中科院分区：
文献类型：
--
作者：
Matsuda, M;Sugo, T
纤维蛋白原是一种340-kDa的血浆蛋白，由两个相同的分子半体组成，每个分子半体由三个不相同的亚基多肽组成，称为A α、B β和γ链，通过多个二硫键连接在一起。纤维蛋白原具有三结节结构，即，一个中央E结构域，其包围配对的单独三个多肽的氨基末端区域，和两个相同的外部D结构域。这三个结节由两个卷曲螺旋区域连接[1，2]。在用凝血酶活化后，由Gly-Pro-Arg组成的三肽片段暴露在位于E结构域中心的每个α链的氨基末端，并与位于另一分子的外部D结构域中的γ链的羧基末端区域中的其互补结合位点（称为“a”位点）结合。通过晶体学分析[3]，显示α Gly-1的α-氨基并置在γ Asp-364的羧基和Gln-329的羧基酰胺之间的“a”位点。因此形成半分子交错的双链纤维蛋白原纤维[4，5]。在同一条链上的两个相邻D结构域邻接时，发生D-D自缔合，涉及邻接的两个D结构域表面上的γ链的Arg-275、Tyr-280和Ser-300 [3]。此后，认为纤维蛋白α链的羧基末端区域未被束缚，并与其他原纤维的羧基末端区域相互作用，导致在适当分支后形成厚纤维蛋白束和交织网络[6-9]。虽然这些分子间相互作用的机制仍有许多谜团，但纤维蛋白组装是以高度有序的方式进行的。在我的演讲中，我想讨论这些纤维蛋白原和纤维蛋白的分子相互作用的基础上提供的最新数据分析正常以及遗传性纤维蛋白原异常，特别是在后者通过引入代表性的分子在纤维蛋白凝块形成的每一步。
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 alpha -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.