8xm7

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

spinqualitylabelsall models 8xm7, resolution 4.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xm7 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.91Å Ligands: GTP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RHOG_HUMAN Defects in RHOG may be the cause of a severe hemophagocytic lymphohistiocytosis (HLH). The affected patient shows characteristic HLH features, such as hemophagocytosis, hepatosplenomegaly, fever, cytopenias, low hemoglobin, hypertriglyceridemia, and elevated ferritin and soluble interleukin-2 receptor. Function RHOG_HUMAN Plays a role in immunological synaptic F-actin density and architecture organization (PubMed:33513601). Regulates actin reorganization in lymphocytes, possibly through the modulation of Rac1 activity (PubMed:33513601). Required for the formation of membrane ruffles during macropinocytosis (PubMed:15133129). Plays a role in cell migration and is required for the formation of cup-like structures during trans-endothelial migration of leukocytes (PubMed:17875742). Binds phospholipids in an activation-dependent manner; thereby acting as an anchor for other proteins to the plasma membrane (PM) (PubMed:33513601). Plays a role in exocytosis of cytotoxic granules (CG) by lymphocytes/Component of the exocytosis machinery in natural killer (NK) and CD8+ T cells (PubMed:33513601). Promotes the docking of cytotoxic granules (CG) to the plasma membrane through the interaction with UNC13D (PubMed:33513601). Involved in the cytotoxic activity of lymphocytes/primary CD8+ T cells (PubMed:33513601). (Microbial infection) In case of Salmonella enterica infection, activated by SopB and ARHGEF26/SGEF, which induces cytoskeleton rearrangements and promotes bacterial entry. Publication Abstract from PubMed 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. RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.,Kukimoto-Niino M, Katsura K, Ishizuka-Katsura Y, Mishima-Tsumagari C, Yonemochi M, Inoue M, Nakagawa R, Kaushik R, Zhang KYJ, Shirouzu M J Biol Chem. 2024 Jun 8;300(7):107459. doi: 10.1016/j.jbc.2024.107459. PMID:38857861 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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