Structural basis of CYRI-B direct competition with Scar/WAVE complex for Rac1

Yelland, T., Le, A. H., Nikolaou, S., Insall, R. , Machesky, L. and Ismail, S. (2021) Structural basis of CYRI-B direct competition with Scar/WAVE complex for Rac1. Structure, 29(3), 226-237.e4. (doi: 10.1016/j.str.2020.11.003) (PMID:33217330) (PMCID:PMC7955166)

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Rac1 is a major regulator of actin dynamics, with GTP-bound Rac1 promoting actin assembly via the Scar/WAVE complex. CYRI competes with Scar/WAVE for interaction with Rac1 in a feedback loop regulating actin dynamics. Here, we reveal the nature of the CYRI-Rac1 interaction, through crystal structures of CYRI-B lacking the N-terminal helix (CYRI-BΔN) and the CYRI-BΔN:Rac1Q61L complex, providing the molecular basis for CYRI-B regulation of the Scar/WAVE complex. We reveal CYRI-B as having two subdomains - an N-terminal Rac1 binding subdomain with a unique Rac1-effector interface and a C-terminal Ratchet subdomain that undergoes conformational changes induced by Rac1 binding. Finally, we show that the CYRI protein family, CYRI-A and CYRI-B can produce an autoinhibited hetero- or homodimers, adding an additional layer of regulation to Rac1 signaling.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK core funding number A17196.
Glasgow Author(s) Enlighten ID:Machesky, Professor Laura and Insall, Professor Robert and Ismail, Dr Shehab and Nikolaou, Savvas
Authors: Yelland, T., Le, A. H., Nikolaou, S., Insall, R., Machesky, L., and Ismail, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Structure
ISSN (Online):1878-4186
Published Online:19 November 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Structure 29(3):226-237.e4
Publisher Policy:Reproduced under a Creative Commons Licence

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