STRUCTURAL BIOLOGY OF ACTIN CROSSLINKING PROTEINS

Project: Research project

Project Details

Description

DESCRIPTION: Filamentous actin assembles into a number of higher order structures with unique physicochemical properties which control cytokinesis, cell and substrate adhesion, pseudopod extension in chemotactic and generalized motility, and the establishment and maintenance of cell morphology. The formation of different actin assemblies is controller by the specific biochemical properties of the actin crosslinking proteins which are themselves regulated by calcium fluxes and phosphorylation events. Thus, the crosslinking proteins make these assemblies responsive to the immediate structural and dynamic needs of the cell. The high resolution crystal structures of the actin crosslinking proteins, human fimbrin, human fascin and ABP-30, in combination with biochemical analysis, will identify which amino acids are important for binding actin with those involved in regulation by calcium and phosphorylation. The contributions of these residues will be tested by mutagenesis and biochemical characterization. The in vivo importance of specific biochemical activities will be assessed by the expression of biochemically defined mutants in living cells. Fimbrin is involved in the life cycle of the bacterial parasites Shigella and Listeria and is closely related to the actin binding domain in dystrophin, the defective protein in muscular dystrophy. These studies will provide the first X-ray structure of an actin crosslinking protein which will allow for an extension of existing models of actin bundling and will provide atomic level detail about the actin binding surfaces and the mechanisms which regulate actin assemblies. The expression studies will show the contribution of specific crosslinker properties to the formation and function of specific actin assemblies in vivo.
StatusFinished
Effective start/end date9/30/968/31/02

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases: $251,671.00

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