Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase

• Published in: Nature communications Vol. 13; no. 1; pp. 5444 - 13
• Main Authors: Ding, Bojian, Yang, Sheng, Schaks, Matthias, Liu, Yijun, Brown, Abbigale J., Rottner, Klemens, Chowdhury, Saikat, Chen, Baoyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/106; 14/19; 631/45/612/1228; 631/535/1258/1259; 82/16; 82/83; Actin; Actin-Related Protein 2-3 Complex - metabolism; Actins - metabolism; Binding; Binding sites; Biochemistry; Biological activity; Biology; Cellular structure; Cytoplasm - metabolism; Electron microscopy; Guanosine triphosphatases; Humanities and Social Sciences; Ligands; Microscopy; multidisciplinary; Polymerization; Polypeptides; Proteins; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Science; Science (multidisciplinary); Wiskott-Aldrich Syndrome Protein Family - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33174-3

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.