STRUCTURAL STUDIES OF ACTIN

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

Actin is the most ubiquitous and conserved eukaryotic protein, and plays a central role in motility and the control of cell form. Understanding the structure and function of actin will have an enormous impact in both the study of normal cellular processes, as well as in the study of diseases such as myopathies. While crystal structures exist for monomeric, G-actin, our structural knowledge of filamentuous F-actin has come in large part from electron microscopy. Given that the active form of actin is the filament, understanding the structure and dynamics of the filament in terms of the atomic structure of the monomer has sgreat relevance in such areas as cell motility and muscle contraction. This proposal is aimed at understanding the role of different structural states of actin, as well as the role of these states in the interaction of actin with other proteins, such as myosin, dystrophin, nebulin and calponin. Specifically, questions about allosteric interactions within actin will be explored, as well as questions about filament dynamics. There are now many observations showing that effects of perturbing or modifying the actin structure at one location result in non-local changes elsewhere in the structure, and it is likely that some of these allosteric effects are involved in the regulation of actomyosin motility. There is preliminary evidence that actin filaments may retain a memory of their history, as a consequence of slow transitions between different structural states. Experiments will be conducted to determine if this slow time scale can explain various cooperative aspects of filament dynamics. Since a growing body of evidence suggests that conformational changes in actin are necessary for actomyosin motility, insight that will be gained from these studies is likely to have a very direct bearing on understanding muscle contraction. The main techniques that will be used for these studies are electron microscopy and three- dimensional reconstruction, but this work will be done in collaboration with with spectroscopic, biochemical and genetic studies.