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

1. 遗传性异常纤维蛋白原的结构-功能关系研究：日本及国外各机构向我们提供了10余份样本，并已完成分析报告（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)马尔堡纤维蛋白原：该纤维蛋白原异常见于一位20岁的德国女性，她表现为术后严重出血，血栓栓塞性疾病复发，愈合障碍，显然与纤维蛋白原功能异常有关。由于AAA编码α Lys-461的终止密码子TAA过早出现，该分子具有一对150个残基截断的α链。由于α -链c端（461-610）残基的截断，α - Cys-442失去了它的二硫桥伙伴，部分地与血清白蛋白二硫桥接。在凝血酶、凝血因子XIII和…More Ca^<2+>的作用下，部分α -连接白蛋白与另一种纤维蛋白分子的γ链交联。交联纤维蛋白被发现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)新ata纤维蛋白原：由于bβ -160的Asn到Ser突变，在bβ 158-159-160产生了一个新的Asn- x -Ser型序列，并且确实发现了一个双天线寡糖与bβ Asn-158有n连锁。由于该突变片段在空间上与D结构域的初级聚合位点分开，我们一直在寻找功能异常的机制。异常纤维蛋白凝块的超微结构分析：与美国的两位专家Michael W.Mosesson和John W.Weisel合作，我们获得了一些重要的代表性分子的信息，这些分子被选择用于我们的国际合作研究。发现马尔堡纤维蛋白凝块由非常薄且高度分枝的纤维组成，从而产生紧密交织的纹理。液体渗透性研究表明，马尔堡纤维蛋白会使液体在其结构中流动得远不如正常对照顺畅。血栓栓塞性疾病和愈合障碍似乎部分归因于这种异常。新泻纤维蛋白凝块由高度支化的纤维蛋白纤维组成，仓氏纤维蛋白凝块与正常凝块相比呈不规则状。在去除低聚糖后，发现新泻纤维蛋白纤维异常粗，并且远少于对照纤维的分支。构造变化与这些异常特征的相关性目前正在调查中。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