|Entry||Database: PDB / ID: 6tgc|
|Title||CryoEM structure of the ternary DOCK2-ELMO1-RAC1 complex|
|Keywords||SIGNALING PROTEIN / guanine nucleotide exchange factor / cytoskeleton / actin / cryoEM|
|Function / homology|
Function and homology information
alpha-beta T cell proliferation / membrane raft polarization / myeloid dendritic cell activation involved in immune response / establishment of T cell polarity / macropinocytosis / regulation of respiratory burst / regulation of neutrophil migration / negative regulation of interleukin-23 production / localization within membrane / immunological synapse formation ...alpha-beta T cell proliferation / membrane raft polarization / myeloid dendritic cell activation involved in immune response / establishment of T cell polarity / macropinocytosis / regulation of respiratory burst / regulation of neutrophil migration / negative regulation of interleukin-23 production / localization within membrane / immunological synapse formation / Activated NTRK2 signals through CDK5 / NADPH oxidase complex / negative regulation of receptor-mediated endocytosis / engulfment of apoptotic cell / regulation of hydrogen peroxide metabolic process / ruffle assembly / NTRK2 activates RAC1 / Rho GDP-dissociation inhibitor binding / negative thymic T cell selection / Inactivation of CDC42 and RAC1 / WNT5:FZD7-mediated leishmania damping / guanyl-nucleotide exchange factor complex / respiratory burst / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / myoblast fusion / PCP/CE pathway / cell projection assembly / RHO GTPases activate CIT / RHO GTPases activate KTN1 / positive thymic T cell selection / cortical cytoskeleton organization / ruffle organization / hepatocyte growth factor receptor signaling pathway / positive regulation of neutrophil chemotaxis / Azathioprine ADME / regulation of stress fiber assembly / negative regulation of fibroblast migration / sphingosine-1-phosphate receptor signaling pathway / thioesterase binding / regulation of nitric oxide biosynthetic process / Wnt signaling pathway, planar cell polarity pathway / regulation of lamellipodium assembly / Nef and signal transduction / motor neuron axon guidance / Sema4D mediated inhibition of cell attachment and migration / Activation of RAC1 / regulation of small GTPase mediated signal transduction / positive regulation of Rho protein signal transduction / Ephrin signaling / positive regulation of cell-substrate adhesion / MET activates RAP1 and RAC1 / DCC mediated attractive signaling / CD28 dependent Vav1 pathway / lamellipodium assembly / Activation of RAC1 downstream of NMDARs / semaphorin-plexin signaling pathway / NRAGE signals death through JNK / regulation of cell size / Rac protein signal transduction / DSCAM interactions / positive regulation of lamellipodium assembly / establishment or maintenance of cell polarity / small GTPase mediated signal transduction / RHO GTPases activate PAKs / ficolin-1-rich granule membrane / regulation of catalytic activity / RHOA GTPase cycle / positive regulation of focal adhesion assembly / RHOG GTPase cycle / Sema3A PAK dependent Axon repulsion / EPH-ephrin mediated repulsion of cells / RHO GTPases activate IQGAPs / anatomical structure morphogenesis / RAC2 GTPase cycle / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / RHO GTPases Activate WASPs and WAVEs / RHO GTPases Activate NADPH Oxidases / RHO GTPases activate PKNs / localization / regulation of actin cytoskeleton organization / GPVI-mediated activation cascade / EPHB-mediated forward signaling / positive regulation of microtubule polymerization / G protein activity / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / regulation of cell migration / RAC1 GTPase cycle / positive regulation of phagocytosis / neuron migration / GTPase activator activity / actin filament polymerization / small monomeric GTPase / guanyl-nucleotide exchange factor activity / cell motility / actin filament organization / cell-matrix adhesion / substrate adhesion-dependent cell spreading / T cell receptor binding / phagocytosis, engulfment
Similarity search - Function
Dedicator of cytokinesis protein 2 / Engulfment and cell motility protein 1 / Dedicator of cytokinesis, N-terminal domain / Dedicator of cytokinesis, N-terminal, subdomain 1 / DOCK N-terminus / ELMO domain / ELMO/CED-12 family / ELMO domain profile. / ELMO, armadillo-like helical domain / ELMO, armadillo-like helical domain ...Dedicator of cytokinesis protein 2 / Engulfment and cell motility protein 1 / Dedicator of cytokinesis, N-terminal domain / Dedicator of cytokinesis, N-terminal, subdomain 1 / DOCK N-terminus / ELMO domain / ELMO/CED-12 family / ELMO domain profile. / ELMO, armadillo-like helical domain / ELMO, armadillo-like helical domain / DOCKER, Lobe A / DOCKER, Lobe B / DOCKER, Lobe C / DHR-2, Lobe C / DHR-2, Lobe B / Dedicator of cytokinesis / C2 DOCK-type domain / DOCKER domain / Dedicator of cytokinesis, C-terminal, lobe A / Dedicator of cytokinesis, C-terminal, lobe C / DHR-2, Lobe A / C2 domain in Dock180 and Zizimin proteins / C2 DOCK-type domain profile. / DOCKER domain profile. / Pleckstrin homology domain / small GTPase Rho family profile. / Small GTPase Rho / Variant SH3 domain / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Pleckstrin homology domain / Small GTPase / Ras family / Src homology 3 domains / Armadillo-like helical / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Small GTP-binding protein domain / PH-like domain superfamily / Armadillo-type fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Ras-related C3 botulinum toxin substrate 1 / Engulfment and cell motility protein 1 / Dedicator of cytokinesis protein 2
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å|
|Authors||Chang, L. / Yang, J. / Chang, J.H. / Zhang, Z. / Boland, A. / McLaughlin, S.H. / Abu-Thuraia, A. / Killoran, R.C. / Smith, M.J. / Cote, J.F. / Barford, D.|
|Funding support|| United Kingdom, 3items |
|Citation||Journal: Nat Commun / Year: 2020|
Title: Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state.
Authors: Leifu Chang / Jing Yang / Chang Hwa Jo / Andreas Boland / Ziguo Zhang / Stephen H McLaughlin / Afnan Abu-Thuraia / Ryan C Killoran / Matthew J Smith / Jean-Francois Côté / David Barford /
Abstract: DOCK (dedicator of cytokinesis) proteins are multidomain guanine nucleotide exchange factors (GEFs) for RHO GTPases that regulate intracellular actin dynamics. DOCK proteins share catalytic (DOCK) ...DOCK (dedicator of cytokinesis) proteins are multidomain guanine nucleotide exchange factors (GEFs) for RHO GTPases that regulate intracellular actin dynamics. DOCK proteins share catalytic (DOCK) and membrane-associated (DOCK) domains. The structurally-related DOCK1 and DOCK2 GEFs are specific for RAC, and require ELMO (engulfment and cell motility) proteins for function. The N-terminal RAS-binding domain (RBD) of ELMO (ELMO) interacts with RHOG to modulate DOCK1/2 activity. Here, we determine the cryo-EM structures of DOCK2-ELMO1 alone, and as a ternary complex with RAC1, together with the crystal structure of a RHOG-ELMO2 complex. The binary DOCK2-ELMO1 complex adopts a closed, auto-inhibited conformation. Relief of auto-inhibition to an active, open state, due to a conformational change of the ELMO1 subunit, exposes binding sites for RAC1 on DOCK2, and RHOG and BAI GPCRs on ELMO1. Our structure explains how up-stream effectors, including DOCK2 and ELMO1 phosphorylation, destabilise the auto-inhibited state to promote an active GEF.
|Structure viewer||Molecule: |
Downloads & links
A: Dedicator of cytokinesis protein 2
B: Engulfment and cell motility protein 1
C: Ras-related C3 botulinum toxin substrate 1
D: Dedicator of cytokinesis protein 2
E: Engulfment and cell motility protein 1
F: Ras-related C3 botulinum toxin substrate 1
Mass: 195902.516 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOCK2, KIAA0209 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q92608
Mass: 83891.328 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELMO1, KIAA0281 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q92556
Mass: 21478.113 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAC1, TC25, MIG5 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63000, small monomeric GTPase
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Ternary complex of DOCK2-ELMO1-RAC1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT|
|Molecular weight||Value: 0.6 MDa / Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Trichoplusia ni (cabbage looper)|
|Buffer solution||pH: 8|
|Specimen||Conc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|EM imaging optics||Energyfilter name: GIF Quantum ER / Energyfilter slit width: 20 eV|
|Image scans||Movie frames/image: 20|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: C1 (asymmetric)|
|3D reconstruction||Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 245763 / Symmetry type: POINT|
|Refinement||Cross valid method: NONE|
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
|Displacement parameters||Biso mean: 538.5 Å2|
|Refine LS restraints|
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