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- PDB-8zji: Structure of DOCK5/ELMO1/Rac1 core (RhoG/DOCK5/ELMO1/Rac1 dataset... -

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Basic information

Entry
Database: PDB / ID: 8zji
TitleStructure of DOCK5/ELMO1/Rac1 core (RhoG/DOCK5/ELMO1/Rac1 dataset, class 1)
Components
  • Dedicator of cytokinesis protein 5
  • Engulfment and cell motility protein 1
  • Ras-related C3 botulinum toxin substrate 1
KeywordsSIGNALING PROTEIN / ELMO / DOCK / GEF / GTPASE / RHO / RAC
Function / homology
Function and homology information


negative regulation of vascular associated smooth muscle contraction / regulation of respiratory burst / negative regulation of interleukin-23 production / regulation of neutrophil migration / localization within membrane / podosome assembly / Activated NTRK2 signals through CDK5 / negative regulation of receptor-mediated endocytosis / regulation of hydrogen peroxide metabolic process / ruffle assembly ...negative regulation of vascular associated smooth muscle contraction / regulation of respiratory burst / negative regulation of interleukin-23 production / regulation of neutrophil migration / localization within membrane / podosome assembly / Activated NTRK2 signals through CDK5 / negative regulation of receptor-mediated endocytosis / regulation of hydrogen peroxide metabolic process / ruffle assembly / NTRK2 activates RAC1 / Inactivation of CDC42 and RAC1 / NADPH oxidase complex / engulfment of apoptotic cell / WNT5:FZD7-mediated leishmania damping / respiratory burst / guanyl-nucleotide exchange factor complex / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / cortical cytoskeleton organization / hepatocyte growth factor receptor signaling pathway / bone remodeling / myoblast fusion / ruffle organization / thioesterase binding / regulation of stress fiber assembly / negative regulation of fibroblast migration / cell projection assembly / RHO GTPases activate CIT / sphingosine-1-phosphate receptor signaling pathway / Nef and signal transduction / positive regulation of vascular associated smooth muscle cell migration / regulation of nitric oxide biosynthetic process / PCP/CE pathway / podosome / positive regulation of neutrophil chemotaxis / RHO GTPases activate KTN1 / Activation of RAC1 / motor neuron axon guidance / regulation of lamellipodium assembly / Azathioprine ADME / anchoring junction / MET activates RAP1 and RAC1 / positive regulation of cell-substrate adhesion / DCC mediated attractive signaling / Wnt signaling pathway, planar cell polarity pathway / Sema4D mediated inhibition of cell attachment and migration / CD28 dependent Vav1 pathway / Ephrin signaling / lamellipodium assembly / regulation of cell size / establishment or maintenance of cell polarity / DSCAM interactions / Activation of RAC1 downstream of NMDARs / small GTPase-mediated signal transduction / Rho GDP-dissociation inhibitor binding / phagocytosis, engulfment / positive regulation of Rho protein signal transduction / NRAGE signals death through JNK / positive regulation of epithelial cell migration / Rac protein signal transduction / RHO GTPases activate PAKs / positive regulation of focal adhesion assembly / semaphorin-plexin signaling pathway / Sema3A PAK dependent Axon repulsion / ficolin-1-rich granule membrane / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / RHO GTPases Activate NADPH Oxidases / RHO GTPases Activate WASPs and WAVEs / localization / RHO GTPases activate IQGAPs / anatomical structure morphogenesis / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / positive regulation of lamellipodium assembly / positive regulation of substrate adhesion-dependent cell spreading / RHO GTPases activate PKNs / regulation of cell migration / positive regulation of microtubule polymerization / positive regulation of stress fiber assembly / GPVI-mediated activation cascade / RAC1 GTPase cycle / EPHB-mediated forward signaling / actin filament polymerization / positive regulation of endothelial cell migration / substrate adhesion-dependent cell spreading / GTPase activator activity / guanyl-nucleotide exchange factor activity / cell-matrix adhesion / cell chemotaxis / small monomeric GTPase / secretory granule membrane / VEGFR2 mediated vascular permeability / G protein activity / Signal transduction by L1 / cell projection / Translocation of SLC2A4 (GLUT4) to the plasma membrane / RHO GTPases Activate Formins / cell motility / regulation of actin cytoskeleton organization / actin filament organization
Similarity search - Function
: / Dedicator of cytokinesis protein 5 / 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 5 / 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 / small GTPase Rho family profile. / C2 domain superfamily / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / SH3 domain / Small GTPase / Ras family / Rab subfamily of small GTPases / Src homology 3 domains / 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 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.23 Å
AuthorsKukimoto-Niino, M. / Katsura, K. / Ishizuka-Katsura, Y. / Mishima-Tsumagari, C. / Yonemochi, M. / Inoue, M. / Nakagawa, R. / Kaushik, R. / Zhang, K.Y.J. / Shirouzu, M.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)KAKENHI JP19K06575 Japan
Japan Society for the Promotion of Science (JSPS)KAKENHI JP22KH05551 Japan
Japan Science and TechnologyCREST JPMJCR22E3 Japan
CitationJournal: J Biol Chem / Year: 2024
Title: RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state.
Authors: Mutsuko Kukimoto-Niino / Kazushige Katsura / Yoshiko Ishizuka-Katsura / Chiemi Mishima-Tsumagari / Mayumi Yonemochi / Mio Inoue / Reiko Nakagawa / Rahul Kaushik / Kam Y J Zhang / Mikako Shirouzu /
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- ...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.
History
DepositionMay 15, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Engulfment and cell motility protein 1
B: Dedicator of cytokinesis protein 5
C: Ras-related C3 botulinum toxin substrate 1
D: Engulfment and cell motility protein 1
E: Dedicator of cytokinesis protein 5
F: Ras-related C3 botulinum toxin substrate 1


Theoretical massNumber of molelcules
Total (without water)592,1486
Polymers592,1486
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 84337.719 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELMO1, KIAA0281 / Production host: Homo sapiens (human) / References: UniProt: Q92556
#2: Protein Dedicator of cytokinesis protein 5


Mass: 191492.125 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DOCK5 / Production host: Homo sapiens (human) / References: UniProt: Q9H7D0
#3: Protein Ras-related C3 botulinum toxin substrate 1 / Cell migration-inducing gene 5 protein / Ras-like protein TC25 / p21-Rac1


Mass: 20244.258 Da / Num. of mol.: 2 / Mutation: G15A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAC1, TC25, MIG5 / Production host: Escherichia coli (E. coli) / 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: DOCK5/ELMO1/Rac1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding 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 IV / 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 / Nominal magnification: 64000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 11976

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
7UCSF Chimeramodel fitting
9PHENIXmodel refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
12RELION3.1classification
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2483502
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133323 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7DPA

7dpa


Accession code: 7DPA / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00533556
ELECTRON MICROSCOPYf_angle_d0.75745324
ELECTRON MICROSCOPYf_dihedral_angle_d5.8174394
ELECTRON MICROSCOPYf_chiral_restr0.0475024
ELECTRON MICROSCOPYf_plane_restr0.0045796

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