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bioRxiv · 10.1101/2022.05.10.491380

Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase

Ding, B.·Yang, S.·Schaks, M.·Liu, Y.·Brown, A.·Rottner, K.·Chowdhury, S.·Chen, B.
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Abstract

Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites--the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at [~]3 [A] resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2- central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.

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Ding, B., Yang, S., Schaks, M., Liu, Y., Brown, A., Rottner, K., Chowdhury, S., Chen, B.. 2022-05-10. Structures reveal a key mechanism of WAVE Regulatory Complex activation by Rac1 GTPase. https://doi.org/10.1101/2022.05.10.491380

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