Structural Basis of CYRI-B Direct Competition with Scar/WAVE Complex for Rac1

Structure. 2021 Mar 4;29(3):226-237.e4. doi: 10.1016/j.str.2020.11.003. Epub 2020 Nov 19.

Abstract

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.

Keywords: CYRIB; SCAR/WAVE; actin; cytoskeleton; invasion; rho.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Binding Sites
  • COS Cells
  • Chlorocebus aethiops
  • Conserved Sequence
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • rac1 GTP-Binding Protein / chemistry*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CYFIP1 protein, human
  • CYRIB protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • RAC1 protein, human
  • rac1 GTP-Binding Protein