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- PDB-7dpa: Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex -

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Basic information

Entry
Database: PDB / ID: 7dpa
TitleCryo-EM structure of the human ELMO1-DOCK5-Rac1 complex
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


guanyl nucleotide exchange factor activator activity / regulation of vasculogenesis / negative regulation of vascular associated smooth muscle contraction / 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 / localization within membrane / kinocilium ...guanyl nucleotide exchange factor activator activity / regulation of vasculogenesis / negative regulation of vascular associated smooth muscle contraction / 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 / localization within membrane / kinocilium / regulation of cell adhesion involved in heart morphogenesis / ruffle assembly / NTRK2 activates RAC1 / NADPH oxidase complex / Inactivation of CDC42 and RAC1 / engulfment of apoptotic cell / regulation of hydrogen peroxide metabolic process / guanyl-nucleotide exchange factor complex / WNT5:FZD7-mediated leishmania damping / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / cortical cytoskeleton organization / cell projection assembly / respiratory burst / ruffle organization / midbrain dopaminergic neuron differentiation / positive regulation of bicellular tight junction assembly / GTP-dependent protein binding / myoblast fusion / negative regulation of fibroblast migration / thioesterase binding / regulation of lamellipodium assembly / regulation of stress fiber assembly / RHO GTPases activate CIT / Nef and signal transduction / motor neuron axon guidance / Activation of RAC1 / PCP/CE pathway / hepatocyte growth factor receptor signaling pathway / sphingosine-1-phosphate receptor signaling pathway / podosome / RHO GTPases activate KTN1 / regulation of nitric oxide biosynthetic process / DCC mediated attractive signaling / MET activates RAP1 and RAC1 / positive regulation of vascular associated smooth muscle cell migration / Azathioprine ADME / Sema4D mediated inhibition of cell attachment and migration / CD28 dependent Vav1 pathway / Ephrin signaling / positive regulation of neutrophil chemotaxis / Wnt signaling pathway, planar cell polarity pathway / superoxide anion generation / regulation of receptor signaling pathway via JAK-STAT / lamellipodium assembly / phagocytosis, engulfment / NRAGE signals death through JNK / positive regulation of ruffle assembly / forebrain development / small GTPase-mediated signal transduction / Rho GDP-dissociation inhibitor binding / 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 / Rac protein signal transduction / positive regulation of epithelial cell migration / RHO GTPases activate PAKs / Sema3A PAK dependent Axon repulsion / RHOG GTPase cycle / EPH-ephrin mediated repulsion of cells / ficolin-1-rich granule membrane / positive regulation of focal adhesion assembly / regulation of postsynapse assembly / RHO GTPases Activate NADPH Oxidases / anatomical structure morphogenesis / regulation of synaptic vesicle endocytosis / RHO GTPases Activate WASPs and WAVEs / RHO GTPases activate IQGAPs / RHO GTPases activate PKNs / GPVI-mediated activation cascade / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / positive regulation of lamellipodium assembly / phagocytic cup / substrate adhesion-dependent cell spreading / positive regulation of stress fiber assembly / cell projection / RAC1 GTPase cycle / actin filament polymerization / positive regulation of substrate adhesion-dependent cell spreading / EPHB-mediated forward signaling / positive regulation of endothelial cell migration / regulation of cell migration / guanyl-nucleotide exchange factor activity / secretory granule membrane / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cell-matrix adhesion / Signal transduction by L1 / GTPase activator activity / VEGFR2 mediated vascular permeability
Similarity search - Function
Dedicator of cytokinesis protein 5 / : / 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 5 / : / 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. / Small GTPase Rho / Small GTPase Rho domain profile. / C2 domain superfamily / Pleckstrin homology domain / SH3 domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / 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: 3.8 Å
AuthorsKukimoto-Niino, M. / Katsura, K. / Kaushik, R. / Ehara, H. / Yokoyama, T. / Uchikubo-Kamo, T. / Mishima-Tsumagari, C. / Yonemochi, M. / Ikeda, M. / Hanada, K. ...Kukimoto-Niino, M. / Katsura, K. / Kaushik, R. / Ehara, H. / Yokoyama, T. / Uchikubo-Kamo, T. / Mishima-Tsumagari, C. / Yonemochi, M. / Ikeda, M. / Hanada, K. / Zhang, K.Y.J. / Shirouzu, M.
CitationJournal: Sci Adv / Year: 2021
Title: Cryo-EM structure of the human ELMO1-DOCK5-Rac1 complex.
Authors: Mutsuko Kukimoto-Niino / Kazushige Katsura / Rahul Kaushik / Haruhiko Ehara / Takeshi Yokoyama / Tomomi Uchikubo-Kamo / Reiko Nakagawa / Chiemi Mishima-Tsumagari / Mayumi Yonemochi / Mariko ...Authors: Mutsuko Kukimoto-Niino / Kazushige Katsura / Rahul Kaushik / Haruhiko Ehara / Takeshi Yokoyama / Tomomi Uchikubo-Kamo / Reiko Nakagawa / Chiemi Mishima-Tsumagari / Mayumi Yonemochi / Mariko Ikeda / Kazuharu Hanada / Kam Y J Zhang / Mikako Shirouzu /
Abstract: The dedicator of cytokinesis (DOCK) family of guanine nucleotide exchange factors (GEFs) promotes cell motility, phagocytosis, and cancer metastasis through activation of Rho guanosine ...The dedicator of cytokinesis (DOCK) family of guanine nucleotide exchange factors (GEFs) promotes cell motility, phagocytosis, and cancer metastasis through activation of Rho guanosine triphosphatases. Engulfment and cell motility (ELMO) proteins are binding partners of DOCK and regulate Rac activation. Here, we report the cryo-electron microscopy structure of the active ELMO1-DOCK5 complex bound to Rac1 at 3.8-Å resolution. The C-terminal region of ELMO1, including the pleckstrin homology (PH) domain, aids in the binding of the catalytic DOCK homology region 2 (DHR-2) domain of DOCK5 to Rac1 in its nucleotide-free state. A complex α-helical scaffold between ELMO1 and DOCK5 stabilizes the binding of Rac1. Mutagenesis studies revealed that the PH domain of ELMO1 enhances the GEF activity of DOCK5 through specific interactions with Rac1. The structure provides insights into how ELMO modulates the biochemical activity of DOCK and how Rac selectivity is achieved by ELMO.
History
DepositionDec 18, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

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


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


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area19280 Å2
ΔGint-114 kcal/mol
Surface area205930 Å2

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Components

#1: 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
#2: 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
#3: 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

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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: ELMO1-DOCK5-Rac1 / 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
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: OTHER
Electron lensMode: BRIGHT FIELD / Calibrated magnification: 105000 X / Calibrated defocus min: 0.5 nm / Calibrated defocus max: 3 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
4CTFFIND4CTF correction
7Cootmodel fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
11RELION3classification
12RELION3.13D reconstruction
13PHENIX1.18.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2145777
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 149846 / Num. of class averages: 1 / Symmetry type: POINT

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