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

纤维蛋白原结构和功能的分子基础 - 遗传性异常纤维蛋白原的分析及其在研究中的应用

基本信息

批准号：
10044316
负责人：
MATSUDA Michio
金额：
$ 1.15万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1998
资助国家：
日本
起止时间：
1998 至无数据
项目状态：
已结题

项目摘要

Studies on two hereditary dysfibrinogens were conducted in collaboration with Dr. Michael W. Mosesson focusing on electron microscopic analyses. 1) Fbg Niigata was found to have a unique Bβ Asn-160 to Ser substitution with an extra oligosaccharide N-linked to Bβ Asn-150.Although the double-stranded fibrin protofibrils are normally formed, their lateral association is impaired, most probably due to the extra oligosaccharide attached to the coiled-coil region. Indeed, enzymatic deglycosylation resulted in enhancement of fibrin monomer polymerization to a great extent. Scanning electron microscopic analyses of fibrin clots revealed an abnormal architecture, being composed of curvilinear fibrin fibers. After deglycosylation, the fibrin fibers became nearly normal, being straight and appropriately branched. The result together with biochemical and gene analysis data is now under the status of revision in BLOOD. Fibrinogen Marburg from Germany was found in a 20-year-old woman who underwent a Caesarian section on her first delivery at the age of 20.Severe bleeding and successive recurrent thrombo-embolic complications were characteristic. This molecule has a 150-amino acid residue truncation of the Aα-chain, and is partly disulfide-bridged with serum albumin at Aα Cys-442. The Marburg fibrin clots are apparently fragile but totally resistant against plasmin Furthermore, factor XIIIa-crosslinking profiles analyzed by SDS-PAGE manifested several α・β- heteromultimers, not observed in the normal sample. To be noted is that the Aα-chain-linked serum albumin was crosslinked to the g-chain of another fibrin molecules, creating disordered fibrin clots. Scanning electron microscopy showed compact fibrin gels consisting of extremely thin but highly branched fibrin fibers. These findings seem to account for recurrent postoperativethrombo-embolic complications. Part of these results appeared in BLOOD (91 : 3282-3288, 1998) and the remainder is now in preparation for publication.

两个遗传性纤维蛋白原异常的研究是与Michael W.着重于电子显微镜分析。1)Fbg新泻具有独特的Bβ Asn-160对Ser的取代，并在Bβ Asn-150上增加了一个N-连接的寡糖。事实上，酶促去糖基化在很大程度上导致纤维蛋白单体聚合的增强。纤维蛋白凝块的扫描电子显微镜分析显示异常的结构，由曲线纤维蛋白纤维组成。去糖基化后，纤维蛋白纤维变得几乎正常，直的和适当的分支。结果连同生化和基因分析数据目前正在BLOOD中进行修订。纤维蛋白原马尔堡来自德国，发现于一位20岁的女性，她在20岁时第一次分娩时接受剖腹产手术。该分子具有Aα链的150个氨基酸残基截短，并且在Aα Cys-442处与血清白蛋白部分二硫键桥接。马尔堡血纤维蛋白凝块明显易碎，但对纤溶酶完全耐药。此外，通过SDS-PAGE分析的因子XIIIa-交联谱显示了几个α·β-异源多聚体，在正常样品中未观察到。值得注意的是，A α链连接的血清白蛋白与另一种纤维蛋白分子的g链交联，产生无序的纤维蛋白凝块。扫描电子显微镜显示致密的纤维蛋白凝胶组成的极薄，但高度分支的纤维蛋白纤维。这些发现似乎可以解释术后血栓栓塞并发症的复发。这些结果的一部分发表在《血液》（91：3282-3288，1998）上，其余的正在准备发表。