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RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.
Kukimoto-Niino, Mutsuko; Katsura, Kazushige; Ishizuka-Katsura, Yoshiko; Mishima-Tsumagari, Chiemi; Yonemochi, Mayumi; Inoue, Mio; Nakagawa, Reiko; Kaushik, Rahul; Zhang, Kam Y J; Shirouzu, Mikako.
Afiliación
  • Kukimoto-Niino M; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan. Electronic address: kukimoto@riken.jp.
  • Katsura K; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Ishizuka-Katsura Y; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Mishima-Tsumagari C; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Yonemochi M; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Inoue M; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Nakagawa R; Laboratory for Cell-Free Protein Synthesis, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan.
  • Kaushik R; Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Zhang KYJ; Laboratory for Structural Bioinformatics, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan.
  • Shirouzu M; Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan. Electronic address: mikako.shirouzu@riken.jp.
J Biol Chem ; 300(7): 107459, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38857861
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína de Unión al GTP rac1 / Factores de Intercambio de Guanina Nucleótido / Proteínas Adaptadoras Transductoras de Señales Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína de Unión al GTP rac1 / Factores de Intercambio de Guanina Nucleótido / Proteínas Adaptadoras Transductoras de Señales Límite: Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article