STRUCTURAL STUDIES ON HOW FIBRINOGEN IS TRANSFORMED INTO FIBRIN

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。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α和β链的氨基末端片段的释放，其结果是暴露出称为“A-节”和“B-节”的新的氨基末端片段。“A-节”与相邻分子的g链的羧基结构域上的孔相匹配，导致两个分子厚的端对端的原纤维。随后的相互作用之间的“B-旋钮”和孔的同源羧基结构域的p链导致的侧关联的原纤维，并最终成熟的纤维网络，构成纤维蛋白。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“旋钮的合成肽复合。“已经出现了一些非常重要的构象变化，以及一系列不同的晶体堆积排列，这些排列表明在纤维蛋白形成的各个阶段可能会发生什么样的接触。还有几种配合物需要确定其结构。我们还通过比较来自远亲物种（包括鸡和七鳃鳗）的片段D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.