STRUCTURAL STUDIES ON HOW FIBRINOGEN IS TRANSFORMED INTO FIBRIN

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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.