CRYSTALLOGRAPHY OF ACTIN AND RELATED PROTEINS

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It is proposed to determine the high resolution structure of the profilin:actin complex by x-ray crystallography, to establish the packing of the monomeric crystal structure in the helical actin filament, to crystallize villin and villin:actin complexes, and to determine the structures of a range of actin conformers in the profilin:actin crystals. A high resolution chemical structure of actin is essential for a mechanistic understanding of muscular contraction and the process of mechanochemical transduction. Very basic processes like cytokinesis, membrane ruffling, and endocytosis, common to many cells, all involve actin filaments and changes in the state of organization of actin-containing structures. The highly-conserved nature of actin and its widespread distribution in eukaryotic cells in processes where movement is involved, points to a common explanation at the chemical level of description. Knowledge of the actin structure, in both the monomeric and filamentous forms, will be important for unravelling the events involved when a cell, transformed by retroviruses, undergoes dramatic changes in shape. Similarly, during platelet activation, major re-organization of the cytoskeleton occurs. Actin-containing microvilli of the inner intestinal lumen medidate the absorptive process, and structures of these bundles may offer deeper insight into malabsorption diseases such as coeliac syndrome.