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- PDB-6tgc: CryoEM structure of the ternary DOCK2-ELMO1-RAC1 complex. -

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Basic information

Entry
Database: PDB / ID: 6tgc
TitleCryoEM structure of the ternary DOCK2-ELMO1-RAC1 complex.
Components
  • Dedicator of cytokinesis protein 2
  • Engulfment and cell motility protein 1
  • Ras-related C3 botulinum toxin substrate 1
KeywordsSIGNALING PROTEIN / guanine nucleotide exchange factor / cytoskeleton / actin / cryoEM
Function / homology
Function and homology information


regulation of vasculogenesis / guanyl nucleotide exchange factor activator activity / myeloid dendritic cell activation involved in immune response / regulation of respiratory burst / positive regulation of ovarian follicle development / regulation of neutrophil migration / negative regulation of interleukin-23 production / Activated NTRK2 signals through CDK5 / negative regulation of fibroblast migration / ruffle assembly ...regulation of vasculogenesis / guanyl nucleotide exchange factor activator activity / myeloid dendritic cell activation involved in immune response / regulation of respiratory burst / positive regulation of ovarian follicle development / regulation of neutrophil migration / negative regulation of interleukin-23 production / Activated NTRK2 signals through CDK5 / negative regulation of fibroblast migration / ruffle assembly / localization within membrane / kinocilium / regulation of cell adhesion involved in heart morphogenesis / NTRK2 activates RAC1 / NADPH oxidase complex / Inactivation of CDC42 and RAC1 / regulation of hydrogen peroxide metabolic process / Rac protein signal transduction / macropinocytosis / engulfment of apoptotic cell / guanyl-nucleotide exchange factor complex / superoxide anion generation / WNT5:FZD7-mediated leishmania damping / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / respiratory burst / motor neuron axon guidance / ruffle organization / myoblast fusion / positive regulation of bicellular tight junction assembly / GTP-dependent protein binding / midbrain dopaminergic neuron differentiation / regulation of lamellipodium assembly / thioesterase binding / regulation of stress fiber assembly / RHO GTPases activate CIT / regulation of nitric oxide biosynthetic process / regulation of small GTPase mediated signal transduction / Nef and signal transduction / Activation of RAC1 / PCP/CE pathway / hepatocyte growth factor receptor signaling pathway / RHO GTPases activate KTN1 / forebrain development / sphingosine-1-phosphate receptor signaling pathway / DCC mediated attractive signaling / MET activates RAP1 and RAC1 / Azathioprine ADME / Sema4D mediated inhibition of cell attachment and migration / lamellipodium assembly / CD28 dependent Vav1 pathway / Ephrin signaling / positive regulation of neutrophil chemotaxis / Wnt signaling pathway, planar cell polarity pathway / positive regulation of ruffle assembly / phagocytosis, engulfment / regulation of receptor signaling pathway via JAK-STAT / NRAGE signals death through JNK / Rho GDP-dissociation inhibitor binding / small GTPase-mediated signal transduction / Activation of RAC1 downstream of NMDARs / positive regulation of Rho protein signal transduction / pericentriolar material / establishment or maintenance of cell polarity / semaphorin-plexin signaling pathway / RHO GTPases activate PAKs / Sema3A PAK dependent Axon repulsion / RHOG GTPase cycle / SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST) / EPH-ephrin mediated repulsion of cells / regulation of postsynapse assembly / ficolin-1-rich granule membrane / RHOA GTPase cycle / RAC2 GTPase cycle / positive regulation of focal adhesion assembly / RHO GTPases Activate NADPH Oxidases / positive regulation of substrate adhesion-dependent cell spreading / anatomical structure morphogenesis / positive regulation of stress fiber assembly / regulation of synaptic vesicle endocytosis / RHO GTPases Activate WASPs and WAVEs / substrate adhesion-dependent cell spreading / positive regulation of lamellipodium assembly / cell-matrix adhesion / RHO GTPases activate IQGAPs / GPVI-mediated activation cascade / RHO GTPases activate PKNs / T cell receptor binding / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / phagocytic cup / actin filament polymerization / RAC1 GTPase cycle / EPHB-mediated forward signaling / regulation of cell migration / positive regulation of endothelial cell migration / positive regulation of phagocytosis / guanyl-nucleotide exchange factor activity / GTPase activator activity / Activation of STAT3 by cadherin engagement / cell motility / actin filament organization
Similarity search - Function
Dedicator of cytokinesis protein 2 / : / Dedicator of cytokinesis, N-terminal domain / Dedicator of cytokinesis, N-terminal, subdomain 1 / : / DOCK N-terminus / Dedicator of cytokinesis (DOCK) TPR region / ELMO protein N-terminal Ras-binding domain / ELMO domain / ELMO, armadillo-like helical domain ...Dedicator of cytokinesis protein 2 / : / Dedicator of cytokinesis, N-terminal domain / Dedicator of cytokinesis, N-terminal, subdomain 1 / : / DOCK N-terminus / Dedicator of cytokinesis (DOCK) TPR region / ELMO protein N-terminal Ras-binding domain / ELMO domain / ELMO, armadillo-like helical domain / : / ELMO/CED-12 family / ELMO, armadillo-like helical domain / ELMO domain profile. / Pleckstrin homology domain / Dedicator of cytokinesis / C2 DOCK-type domain / DOCKER domain / Dedicator of cytokinesis, C-terminal, lobe A / Dedicator of cytokinesis, C-terminal, lobe C / DOCKER, Lobe A / DOCKER, Lobe B / DOCKER, Lobe C / DHR-2, Lobe A / C2 domain in Dock180 and Zizimin proteins / DHR-2, Lobe C / DHR-2, Lobe B / C2 DOCK-type domain profile. / DOCKER domain profile. / Variant SH3 domain / Small GTPase Rho / Small GTPase Rho domain profile. / C2 domain superfamily / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Src homology 3 domains / Rab subfamily of small GTPases / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-like helical / 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 speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsChang, 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, European Union, 3items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_UP_1201/6 United Kingdom
Cancer Research UKC576/A14109 United Kingdom
Marie Sklodowska-Curie Actions, FragNET ITN657725European Union
CitationJournal: 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.
History
DepositionNov 15, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Structure summary / Category: database_2 / struct
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct.title
Revision 1.2Jul 26, 2023Group: Author supporting evidence / Other / Category: pdbx_audit_support / pdbx_database_status
Item: _pdbx_audit_support.country / _pdbx_database_status.pdb_format_compatible
Revision 1.3Jul 10, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Assembly

Deposited unit
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


Theoretical massNumber of molelcules
Total (without water)602,5446
Polymers602,5446
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18800 Å2
ΔGint-139 kcal/mol
Surface area210600 Å2
MethodPISA

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Components

#1: Protein Dedicator of cytokinesis protein 2


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
#2: Protein Engulfment and cell motility protein 1 / Protein ced-12 homolog


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
#3: Protein Ras-related C3 botulinum toxin substrate 1 / Cell migration-inducing gene 5 protein / Ras-like protein TC25 / p21-Rac1


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

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of DOCK2-ELMO1-RAC1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.6 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHepesC8H18N2O4S1
2200 mMsodium chlorideNaCl1
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum ER / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 20

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.16_3549refinement
PHENIX1.16_3549refinement
EM software
IDNameVersionCategory
1RELION1.4particle selection
2EPUimage acquisition
4GctfCTF correction
13RELION1.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 245763 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 538.5 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.015433882
ELECTRON MICROSCOPYf_angle_d1.789446026
ELECTRON MICROSCOPYf_chiral_restr0.07475416
ELECTRON MICROSCOPYf_plane_restr0.01065930
ELECTRON MICROSCOPYf_dihedral_angle_d15.86320486

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