Structural investigation of Arp2/3 complex activation

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Reorganization of the actin cytoskeleton allows cells to change shape and move in response to environmental cues. Polymerization of actin.is tightly regulated, and the cell maintains an arsenal of proteins to control when, where and how filaments grow. Arp2/3 complex is an assembly of seven proteins that nucleates the growth of new actin filaments in a signal-dependent manner. Nucleation promoting factors link Arp2/3 complex to upstream signals. They bind to Arp2/3 complex, recruit the first actin monomer for the new filament, and promote a activating conformational change in the complex. The goal of this proposal is to use x-ray crystallography to determine the structures of Arp2/3 complex with a bound nucleation promoting factor and with nucleation promoting factor plus actin monomer. These structures will provide a molecular basis for understanding how Arp2/3 complex nucleates the growth of new actin filaments. Furthermore, it will show how nucleation promoting factors activate the complex. This will provide a basis for a better understanding of cytoskeletal function in both normal and diseased states of the cell.