Structural Studies on Fibrinogen and Fibrin

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Description (provided by applicant): The meshwork of a blood clot is composed of fibrin fibers built up by the systematic assembly of fibrinogen molecules that have been proteolyzed by thrombin. During the process, the resulting polymers are further reinforced by the factor XIII-catalyzed introduction of crosslinks between various lysine and glutamine sidechains. Ultimately, the clot is digested by plasmin. The general nature of the clotting and lysis process has been appreciated for several decades, but a detailed knowledge of events was not possible because the three-dimensional structure of the starting fibrinogen units could not be determined at the atomic level. All this has changed during the past three years as a result of a series of high resolution crystal structures of fibrinogen fragments and a low resolution structure of a native fibrinogen. The structures have been very revealing and the possibility of a full understanding no longer seems remote. The immediate goals of this project are to obtain high-resolution crystal structures of native fibrinogens by X-ray diffraction, first of a chicken structure which is already well under way, and then the more daunting human molecule, crystals of which we have only recently observed and which are still too small for useful study. We also propose to solve separately the structure of an elusive but key part of fibrinogen that is very mobile and which has not yielded to other approaches. The proposal also describes plans for determining several complexes that can be isolated from crosslinked fibrin, including a moiety called "D2E." Combined with the full structures of the native molecules at high resolution, these results should dispel much of the mystery of fibrin formation.