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

1.遗传性纤维蛋白原结构与功能关系的研究：从日本和国外的研究机构向我们介绍了10多个样本，目前已完成的分析工作已经报道(见发表名单)。其中，我们想介绍两个独特的分子，一个来自国外，另一个来自新泻。(1)纤维蛋白原Marburg：该异常纤维蛋白原见于一位20岁的德国女性患者，她术后出血严重，反复出现血栓栓塞性疾病，并会出现愈合障碍，这些明显与纤维蛋白原功能异常有关。这种分子有一对150个残基被截断的Aalpha链，这是由于AAA编码AalphaLys-461的终止密码子TAA过早出现而造成的。由于AAlpha链的C末端(461-610)残基的这种截断，AAlpha Cys-442失去了它的二硫键桥联伙伴，并与血清白蛋白部分地二硫键桥联。凝血酶、凝血因子XIII和…的凝血作用更多的钙离子，Aα连接的白蛋白的一部分与另一种纤维蛋白分子的伽马链交联。交联型纤维蛋白被发现对血浆消化有极强的抵抗力，这至少是患者血栓栓塞症并发症的部分原因。(2)纤维蛋白原Niigata：由于Bbeta-160处Asn到Ser的突变，在Bbeta 158-159-160处产生了一个新的Asn-X-Ser型序列，确实，发现了一个与Bbeta ASN-158 N相连的双天线橄榄糖。由于这个突变片段在空间上与D结构域中的初级聚合位点分离，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：我们与美国的两位专家Michael W.Mosesson和John W.Weisel合作，获得了几条关于我们国际合作研究的代表性分子的重要信息。马尔堡纤维凝块被发现由非常薄的高度分叉的纤维组成，这导致了紧密交织的纹理。液体渗透性研究表明，马尔堡纤维蛋白会使液体在其质地中流动得比正常对照组差得多。血栓栓塞性疾病和Will愈合障碍似乎是这种异常的部分原因。Niigata纤维蛋白凝块由高度分枝的纤维蛋白纤维组成，Kurashiki纤维蛋白凝块与正常血栓相比看起来不规则。去除低聚糖后，新泻纤维纤维被发现异常粗大，分支比对照纤维少得多。结构变化与这些异常特征的相关性目前正在调查中。较少

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