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Cited by 59Protein Kinase Regulation and GTPase SignalingCellular transport and secretionReceptor Mechanisms and Signaling

Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

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Chang, Leifu, Yang, Jing, Jo, Chang Hwa, Boland, Andreas, Zhang, Ziguo, McLaughlin, Stephen H., Abu-Thuraia, Afnan, Killoran, Ryan C. +3 more·2020·Nature Communications
DOI 10.1038/s41467-020-17271-9PMC PMC7351999
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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 DHR2) and membrane-associated (DOCK DHR1) 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 RBD) 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 RBD 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 DHR2, 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.

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  • A recent cryo-electron microscopy structure of the full-length DOCK2-RAC1-ELMO1 complex is consistent with prior predictions and provides the first high-resolution view of conformational and phosphorylation events leading to activation of the complete complex.

    “A recent cryo-electron microscopy-derived structure of this signaling complex using the full-length proteins is consistent with these predictions and provides the first high-resolution view of the conformational and phosphorylation events leading to activation of the complete complex (Fig. 3) (38).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [38]

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  • The DOCK-C subfamily has dual binding capability, activating both CDC42 and RAC1, except DOCK8, which appears to be a specific CDC42 GEF.

    “The DOCK-C subfamily has dual binding capability, activating both CDC42 and RAC1, except for DOCK8, which appears to be a specific CDC42 GEF (38).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [38]

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Authors
Chang, L., Yang, J., Jo, C. H., Boland, A., Zhang, Z., McLaughlin, S. H., Abu-Thuraia, A., Killoran, R. C., Smith, M. J., Côté, J.-F., & Barford, D.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • Institute for Research in Immunology and Cancer (CA)
  • University of Geneva (CH)
  • Montreal Clinical Research Institute (CA)
Corresponding author
Barford, David
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-07-10
Volume
11
Issue
1
Pages
3464-3464
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-17271-9
PMC
PMC7351999
OpenAlex
W3041891313
Cited by
59
References
4
Citations by year
2026: 4 · 2025: 7 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 16 · 2020: 3
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
  • Apollo
Funders
  • Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre
  • Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada
  • RCUK | Medical Research Council (MC_UP_1201/6)
  • Cancer Research UK (C576/A14109)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
DOCK2, ELMO1, guanine nucleotide exchange factor, Rac1, Rho GTPases, autoinhibition, Ras-binding domain, RhoG, actin dynamics, protein complex structure, phosphorylation, conformational change
MeSH terms
Calorimetry, HeLa Cells, Humans, Kinetics, Microscopy, Electron, Phosphorylation, Immunoblotting, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, rho GTP-Binding Proteins, rac1 GTP-Binding Protein, Adaptor Proteins, Signal Transducing, HEK293 Cells

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