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Mechanistic study of Arp2/3 complex activation by WASP family proteins

The Arp2/3 complex is a seven-protein complex that is one of the primary actin filament nucleators in cells. It has been well demonstrated that the VCA peptide of proteins in the WASP family activates the Arp2/3 complex toward filament nucleation. But the mechanism through which the VCA acts is only partly understood at the biochemical, structural or kinetic level.

Our initial discovery that Arp2/3 complex is better activated by VCA dimers than by VCA monomers has led into several studies that have greatly improved our understanding of filament nucleation, through several key findings. We have found that WASP proteins use dimerization and oligomerization to integrate multiple signals from upstream effectors. We have found that Arp2/3 complex can independently bind to two VCA peptides, each harboring an actin monomer.

We have developed a structural model for VCA association with Arp2/3 complex and actin monomer delivery. Through the use of bulk and single molecule kinetic studies, we have found that VCA acts at different steps of Arp2/3-mediated nucleation to both promote and prevent formation of a new filament. The combination of all these finding provides a deep, rich understanding of this important protein machinery.

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