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| Title | RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state. |
|---|---|
| Journal, issue, pages | J Biol Chem, Page 107459, Year 2024 |
| Publish date | Jun 8, 2024 |
 Authors | Mutsuko Kukimoto-Niino / Kazushige Katsura / Yoshiko Ishizuka-Katsura / Chiemi Mishima-Tsumagari / Mayumi Yonemochi / Mio Inoue / Reiko Nakagawa / Rahul Kaushik / Kam Y J Zhang / Mikako Shirouzu /  |
| 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- ...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 PIP3 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. |
 External links | J Biol Chem / PubMed:38857861 |
| Methods | EM (single particle) |
| Resolution | 4.23 - 4.91 Å |
| Structure data | EMDB-36271, PDB-8jhk: EMDB-38466, PDB-8xm7: EMDB-60136, PDB-8zj2: EMDB-60146, PDB-8zji: EMDB-60147, PDB-8zjj: EMDB-60148, PDB-8zjk: EMDB-60149, PDB-8zjl: EMDB-60150, PDB-8zjm: |
| Chemicals |  ChemComp-MG:  ChemComp-GTP: |
| Source |
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 Keywords | SIGNALING PROTEIN / ELMO / DOCK / GEF / GTPASE / RHO / RAC |
homo sapiens (human)