8ZJ2

Cryo-EM structure of the RhoG/DOCK5/ELMO1/Rac1 complex

This is a non-PDB format compatible entry.

Summary for 8ZJ2

• Entry DOI: 10.2210/pdb8zj2/pdb
• Related: 8JHK 8XM7
• EMDB information: 60136
• Descriptor: Dedicator of cytokinesis protein 5, Ras-related C3 botulinum toxin substrate 1, Engulfment and cell motility protein 1, ... (6 entities in total)
• Functional Keywords: elmo, dock, gef, gtpase, rho, rac, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 615058.05

Authors

Kukimoto-Niino, M.,Katsura, K.,Ishizuka-Katsura, Y.,Mishima-Tsumagari, C.,Yonemochi, M.,Inoue, M.,Nakagawa, R.,Kaushik, R.,Zhang, K.Y.J.,Shirouzu, M. (deposition date: 2024-05-14, release date: 2024-06-26, Last modification date: 2024-07-17)

Primary citation

Kukimoto-Niino, M.,Katsura, K.,Ishizuka-Katsura, Y.,Mishima-Tsumagari, C.,Yonemochi, M.,Inoue, M.,Nakagawa, R.,Kaushik, R.,Zhang, K.Y.J.,Shirouzu, M.
RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.
J.Biol.Chem., 300:107459-107459, 2024

PubMed Abstract: The dedicator of cytokinesis (DOCK)/engulfment and cell motility (ELMO) complex serves as a guanine nucleotide exchange factor (GEF) for the GTPase Rac. RhoG, another GTPase, activates the ELMO-DOCK-Rac pathway during engulfment and migration. Recent cryo-EM structures of the DOCK2/ELMO1 and DOCK2/ELMO1/Rac1 complexes have identified closed and open conformations that are key to understanding the autoinhibition mechanism. Nevertheless, the structural details of RhoG-mediated activation of the DOCK/ELMO complex remain elusive. Herein, we present cryo-EM structures of DOCK5/ELMO1 alone and in complex with RhoG and Rac1. The DOCK5/ELMO1 structure exhibits a closed conformation similar to that of DOCK2/ELMO1, suggesting a shared regulatory mechanism of the autoinhibitory state across DOCK-A/B subfamilies (DOCK1-5). Conversely, the RhoG/DOCK5/ELMO1/Rac1 complex adopts an open conformation that differs from that of the DOCK2/ELMO1/Rac1 complex, with RhoG binding to both ELMO1 and DOCK5. The alignment of the DOCK5 phosphatidylinositol (3,4,5)-trisphosphate binding site with the RhoG C-terminal lipidation site suggests simultaneous binding of RhoG and DOCK5/ELMO1 to the plasma membrane. Structural comparison of the apo and RhoG-bound states revealed that RhoG facilitates a closed-to-open state conformational change of DOCK5/ELMO1. Biochemical and surface plasmon resonance (SPR) assays confirm that RhoG enhances the Rac GEF activity of DOCK5/ELMO1 and increases its binding affinity for Rac1. Further analysis of structural variability underscored the conformational flexibility of the DOCK5/ELMO1/Rac1 complex core, potentially facilitating the proximity of the DOCK5 GEF domain to the plasma membrane. These findings elucidate the structural mechanism underlying the RhoG-induced allosteric activation and membrane binding of the DOCK/ELMO complex.

PubMed: 38857861
DOI: 10.1016/j.jbc.2024.107459

Experimental method

ELECTRON MICROSCOPY (4.66 Å)