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- Title
Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase.
- Authors
Ding, Bojian; Yang, Sheng; Schaks, Matthias; Liu, Yijun; Brown, Abbigale J.; Rottner, Klemens; Chowdhury, Saikat; Chen, Baoyu
- Abstract
The Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-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 Å 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. Rho-family GTPase Rac1 activates the WAVE complex (WRC) to promote Arp2/3-mediated actin assembly in various processes. Here, the authors determined cryo-EM structures of WRC bound to Rac1 in different states, revealing how Rac1 binding activates WRC.
- Subjects
GUANOSINE triphosphatase; CELL analysis; BINDING sites
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-33174-3