RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability

DOI: 10.1038/s41556-019-0337-y

Authors: Jessica Diring (The Francis Crick Institute) , Stephane Mouilleron (Cancer Research UK) , Neil Q. Mcdonald (The Francis Crick Institute; Birkbeck College, London) , Richard Treisman (The Francis Crick Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Cell Biology

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 8015

Abstract: RPEL proteins, which contain the G-actin-binding RPEL motif, coordinate cytoskeletal processes with actin dynamics. We show that the ArhGAP12- and ArhGAP32-family GTPase-activating proteins (GAPs) are RPEL proteins. We determine the structure of the ArhGAP12/G-actin complex, and show that G-actin contacts the RPEL motif and GAP domain sequences. G-actin inhibits ArhGAP12 GAP activity, and this requires the G-actin contacts identified in the structure. In B16 melanoma cells, ArhGAP12 suppresses basal Rac and Cdc42 activity, F-actin assembly, invadopodia formation and experimental metastasis. In this setting, ArhGAP12 mutants defective for G-actin binding exhibit more effective downregulation of Rac GTP loading following HGF stimulation and enhanced inhibition of Rac-dependent processes, including invadopodia formation. Potentiation or disruption of the G-actin/ArhGAP12 interaction, by treatment with the actin-binding drugs latrunculin B or cytochalasin D, has corresponding effects on Rac GTP loading. The interaction of G-actin with RPEL-family rhoGAPs thus provides a negative feedback loop that couples Rac activity to actin dynamics.

Journal Keywords: Actin; RHO signalling

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 25/06/2019 10:30

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)