Journal Article

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

Yang, Sheng, Chen, Baoyu, Brown, Abbigale J., Ding, Bojian, Schaks, Matthias, Chowdhury, Saikat, Rottner, Klemens, Liu, Yijun

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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