6GVC

Structure of ArhGAP12 bound to G-Actin

Summary for 6GVC

• Entry DOI: 10.2210/pdb6gvc/pdb
• Descriptor: Actin, alpha skeletal muscle, Rho GTPase-activating protein 12, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: gap, rac, actin, hydrolase
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 8
• Total formula weight: 279271.90

Authors

Mouilleron, S.,Treisman, R.,Diring, J. (deposition date: 2018-06-20, release date: 2019-03-27, Last modification date: 2024-01-17)

Primary citation

Diring, J.,Mouilleron, S.,McDonald, N.Q.,Treisman, R.
RPEL-family rhoGAPs link Rac/Cdc42 GTP loading to G-actin availability.
Nat.Cell Biol., 21:845-855, 2019

PubMed 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.

PubMed: 31209295
DOI: 10.1038/s41556-019-0337-y

Experimental method

X-RAY DIFFRACTION (2.6 Å)