STRUCTURAL STUDIES ON HOW FIBRINOGEN IS TRANSFORMED INTO FIBRIN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。纤维蛋白原转化为纤维蛋白的起始事件是凝血酶催化的纤维蛋白肽A和B从A和p链的氨基末端片段释放，其结果是暴露新的氨基末端片段，称为“A旋钮”和“B旋钮”。“a旋钮”与相邻分子的g链羧基结构域上的孔吻合，形成两分子厚的端到端原纤维。随后，“b旋钮”和p链同源羧基结构域上的孔之间的相互作用导致原原纤维的横向结合，并最终形成构成纤维蛋白的成熟纤维网络。除了我们对天然纤维蛋白原的研究外，我们还确定了具有“孔”的片段D区域的结构，该区域与模拟A和B“旋钮”的合成肽络合。一些非常重要的构象变化已经出现，以及一系列不同的晶体排列，这些排列表明在纤维蛋白形成的不同阶段可能发生了什么接触。还有几个复合体的结构需要确定。我们还通过比较远亲物种（包括鸡和七鳃鳗）的D片段的结构来了解这一过程。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The initiating event in the conversion of fibrinogen to fibrin is the thrombin-catalyzed release of fibrinopeptides A and B from the amino-terminal segments of the a and p chains, the consequence of which is the exposure of new amino-terminal segments known as the "A-knobs" and "B-knobs." The "A-knobs" fit into holes on the carboxyl domains of g chains of neighboring molecules, leading to a two-molecule thick, end-to-end protofibril. Subsequent interactions between the "B-knobs" and holes on the homologous carboxyl domains of p chains lead to the lateral association of the protofibrils and, eventually to the mature fiber network which constitutes fibrin. In addition to our studies on native fibrinogens, we have been determining the structures of the fragment D regions that have the "holes," complexed with synthetic peptides that simulate the A and B "knobs." Some very significant conformational changes have emerged, as well as a series of different crystal packing arrangements that suggest what contacts may be made during the various stages of fibrin formation. Several more of the complexes need their structures determined. We are also gaining insights about the process by comparing the structures of fragments D from distantly related species, including chicken and lamprey.