Molecular basis for the fibrinogen structure and functions-Analysis of hereditary dysfibrinogens and their application to the study

1.遗传性纤维蛋白原异常的结构-功能关系的研究：从日本和国外的研究机构获得了10多个样品，并报告了迄今为止完成的分析（见出版物列表）。其中，我们想介绍两种独特的分子，一种来自国外，另一种来自新泻。(1)纤维蛋白原马尔堡：这种纤维蛋白原异常是在一位20岁的德国女士身上发现的，她表现为严重的术后出血、复发性血栓栓塞性疾病和愈合障碍，所有这些显然都与纤维蛋白原功能异常有关。由于编码Aalpha Lys-461的AAA的终止密码子TAA过早出现，该分子具有一对150个残基截短的Aalpha链。由于A α链的C-末端（461-610）残基的这种截短，A α Cys-442失去了其二硫键桥配偶体，并且与血清白蛋白部分二硫键桥连。凝血酶、凝血因子XIII和 ...更多信息 Ca^<2+>，A α连接的白蛋白的一部分与另一种纤维蛋白分子的γ链交联。发现交联纤维蛋白对血浆消化具有极强的抵抗力，至少部分解释了患者的血栓栓塞并发症。(2)纤维蛋白原新泻：由于Bbeta-160处的Asn突变为Ser，在Bbeta 158-159-160处产生了新的Asn-X-Ser型序列，并且确实发现双触角寡糖与Bbeta Asn-158 N-连接。由于该突变片段在空间上与D结构域中的主要聚合位点分离，我们一直在寻找功能异常的潜在机制。异常纤维蛋白凝块的超微结构分析：与美国两位专家合作，Michael W.Mosesson和John W.Weisel，我们已经获得了几个重要的信息，为我们的国际合作研究选择的代表性分子。发现马尔堡纤维蛋白凝块由非常细和高度分支的纤维组成，其产生紧密交织的纹理。液体渗透性研究表明，马尔堡纤维蛋白使液体在其质地中的流动远不如在正常对照中顺畅。血栓栓塞性疾病和伤口愈合障碍似乎部分是由这种异常。新泻纤维蛋白凝块由高度分支的纤维蛋白纤维组成，仓敷纤维蛋白凝块与正常凝块相比似乎不规则。去除低聚糖后，发现新泻纤维蛋白纤维比对照纤维格外粗且分支少得多。目前正在调查这些异常特征的结构变化的相关性。少

1. Studies on the structure-function relationship of hereditary dysfibrinogens : More than 10 samples have been referred to us from the institutions in Japan and from abroad, and the analyzes so far completed have been reported (See the publication list). Among them, we would like to introduce two unique molecules, one from abroad and the other from Niigata. (1) Fibrinogen Marburg : This dysfibrinogen was found in a 20 year-old German lady who manifested severe post-operative bleeding, recurrent thrombo-embolic diseases and would healing disturbance, all apparently related to functional abnormalities of fibrinogen. This molecule has a pair of 150 residues-truncated Aalpha-chains due to premature appearance of a stop codon TAA for AAA coding Aalpha Lys-461. Because of this truncation of the C-terminal (461-610) residues of the Aalpha-chain, Aalpha Cys-442 has lost its disulfide-bridge partner, and is partly disulfide-bridged with serum albumin. On clotting with thrombin, factor XIII and … More Ca^<2+>, part of the Aalpha-linked albumin was cross-linked to the gamma-chain of another fibrin molecules. The cross-linked fibrin was found to be extremely resistant against plasmic digestion, accounting for at least partly the thrombo-embolic complications in the patient. (2) Fibrinogen Niigata : Because of an Asn to Ser mutation at Bbeta-160, a new Asn-X-Ser type sequence is created at Bbeta 158-159-160, and indeed, a biantennary olibosaccharide was found to be N-linked to Bbeta Asn-158. As this mutant segment is spatially apart from the primary polymerization site in the D domain, we have been searching for the mechanism underlying functional abnormalities.2. Analyzes of the ultrastructure of the abnormal fibrin clots : In collaboration with two experts in U.S.A., Michael W.Mosesson and John W.Weisel, we have obtained several important pieces of information on representative molecules selected for our international collaboration studis. The Marburg fibrin clots were found to consist of very thin and highly branched fibers, which give rise to compactly interwoven textures. Liquid permeability studies showed that the Marburg fibrin would allow liquids to flow far less smoothly in their textures than in th normal contrl. The thrombo-embolic diseases and would healing disturbances seem to be partly accounted for by this abnormality. The Niigata fibrin clots were composed of highly branched fibrin fibers and the Kurashiki fibrin clots appeared to be irregular as compared with the normal clots. After removal of the oligosaccharides, the Niigata fibrin fibers were found to be extraordinarily thick and far less branched than the control fibers. The relevance of the structural alteration to these abnormal features are currently under investigation. Less