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- PDB-8jhk: Cryo-EM structure of the DOCK5/ELMO1 complex, focused on one protomer -

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Basic information

Entry
Database: PDB / ID: 8jhk
TitleCryo-EM structure of the DOCK5/ELMO1 complex, focused on one protomer
Components
  • Dedicator of cytokinesis protein 5
  • Engulfment and cell motility protein 1
KeywordsSIGNALING PROTEIN / ELMO / DOCK / GEF / GTPASE / RHO / RAC
Function / homology
Function and homology information


negative regulation of vascular associated smooth muscle contraction / podosome assembly / guanyl-nucleotide exchange factor complex / bone remodeling / myoblast fusion / Nef and signal transduction / positive regulation of vascular associated smooth muscle cell migration / podosome / anchoring junction / phagocytosis, engulfment ...negative regulation of vascular associated smooth muscle contraction / podosome assembly / guanyl-nucleotide exchange factor complex / bone remodeling / myoblast fusion / Nef and signal transduction / positive regulation of vascular associated smooth muscle cell migration / podosome / anchoring junction / phagocytosis, engulfment / positive regulation of epithelial cell migration / Rac protein signal transduction / RHOG GTPase cycle / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / positive regulation of substrate adhesion-dependent cell spreading / RAC1 GTPase cycle / GTPase activator activity / guanyl-nucleotide exchange factor activity / cell projection / cell motility / actin filament organization / FCGR3A-mediated phagocytosis / Regulation of actin dynamics for phagocytic cup formation / small GTPase binding / VEGFA-VEGFR2 Pathway / SH3 domain binding / cell migration / Factors involved in megakaryocyte development and platelet production / actin cytoskeleton organization / apoptotic process / membrane / plasma membrane / cytoplasm / cytosol
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 / C2 domain superfamily / Pleckstrin homology domain / SH3 domain / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-like helical / PH-like domain superfamily / Armadillo-type fold
Similarity search - Domain/homology
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: 4.76 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 JP22H05551 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 PIP3 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 23, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 29, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Engulfment and cell motility protein 1
B: Dedicator of cytokinesis protein 5
E: Dedicator of cytokinesis protein 5


Theoretical massNumber of molelcules
Total (without water)467,3223
Polymers467,3223
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
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.: 1
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

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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 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: 6303

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2EPUimage acquisition
7UCSF Chimeramodel fitting
12RELION3.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 279838 / Num. of class averages: 2 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
17DPA

7dpa

17DPA1PDBexperimental model
26IE1

6ie1

16IE12PDBexperimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00620937
ELECTRON MICROSCOPYf_angle_d0.90528247
ELECTRON MICROSCOPYf_dihedral_angle_d9.6242731
ELECTRON MICROSCOPYf_chiral_restr0.0513118
ELECTRON MICROSCOPYf_plane_restr0.0063616

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