View source for 8xm7


==Cryo-EM structure of the RhoG/DOCK5/ELMO1/Rac1 complex: RhoG/DOCK5/ELMO1 focused map==
<StructureSection load='8xm7' size='340' side='right'caption='[[8xm7]], [[Resolution|resolution]] 4.91&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8xm7]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8XM7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XM7 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.91&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8xm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xm7 OCA], [https://pdbe.org/8xm7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xm7 RCSB], [https://www.ebi.ac.uk/pdbsum/8xm7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xm7 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RHOG_HUMAN 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.<ref>PMID:33513601</ref> 
== Function ==
[https://www.uniprot.org/uniprot/RHOG_HUMAN 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).<ref>PMID:15133129</ref> <ref>PMID:17875742</ref> <ref>PMID:33513601</ref>   (Microbial infection) In case of Salmonella enterica infection, activated by SopB and ARHGEF26/SGEF, which induces cytoskeleton rearrangements and promotes bacterial entry.<ref>PMID:17074883</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:38857861</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8xm7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Inoue M]]
[[Category: Ishizuka-Katsura Y]]
[[Category: Katsura K]]
[[Category: Kaushik R]]
[[Category: Kukimoto-Niino M]]
[[Category: Mishima-Tsumagari C]]
[[Category: Nakagawa R]]
[[Category: Shirouzu M]]
[[Category: Yonemochi M]]
[[Category: Zhang KYJ]]