The objective of this program is to determine the precise molecular architecture of a diverse class of Alpha-fibrous proteins whose role is both structural and dynamic. The chief methods are coordinated X-ray crystallography, electron microscopy and image analysis. Muscle proteins are a central focus and provide the background for studying related systems. A major aim is to determine the structure and motions in two calcium-dependent protein switches that control contraction. Thus crystals of the regulatory complex tropomyosin/troponin are being analyzed, and the topology of the myosin molecule with its associated light chains will be determined to establish models for regulation. The molecular basis of blood clotting is being studied by a similar approach. The structure of fibrinogen will be determined by X-ray crystallography and its packing established in the fibrin clot. These structural methods will also be applied to certain cytoskeletal and cell surface proteins (including those on human parasites) that play important roles in cell form, movement and interactions. The broad study of these systems is directed towards identifying distinctive features of structure that are essential to their function. Knowledge of the molecular mechanisms of contraction and its regulation in normal muscle is needed to account for their failure in various heart and muscle diseases. Similarly, a full understanding of blood clotting, and its malfunction in certain cardiovascular diseases, requires detailed information about the structure and interactions of the fibrinogen molecule. We now recognize the vital role of the cytoskelton and various arrays of internal and external cell surface proteins in normal cell function and in development, and the responsiveness of these structures to cell transformation. The occurrence of fibrous proteins that may be related to muscle proteins at the surface of pathogenic organisms has important medical implications. We believe that our broad study of the structure and interactions of these fibrous proteins will lead to a deeper understanding of both normal and abnormal cellular function.
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