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

Author

Listed:
  • Leifu Chang

    (MRC Laboratory of Molecular Biology
    Department of Biological Sciences, Purdue University)

  • Jing Yang

    (MRC Laboratory of Molecular Biology)

  • Chang Hwa Jo

    (Institute for Research in Immunology and Cancer, Université de Montréal)

  • Andreas Boland

    (MRC Laboratory of Molecular Biology
    Department of Molecular Biology, Science III, University of Geneva)

  • Ziguo Zhang

    (MRC Laboratory of Molecular Biology)

  • Stephen H. McLaughlin

    (MRC Laboratory of Molecular Biology)

  • Afnan Abu-Thuraia

    (Montreal Institute of Clinical Research (IRCM))

  • Ryan C. Killoran

    (Institute for Research in Immunology and Cancer, Université de Montréal)

  • Matthew J. Smith

    (Institute for Research in Immunology and Cancer, Université de Montréal
    Université de Montréal)

  • Jean-Francois Côté

    (Montreal Institute of Clinical Research (IRCM)
    Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal
    McGill University)

  • David Barford

    (MRC Laboratory of Molecular Biology)

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 (DOCKDHR2) and membrane-associated (DOCKDHR1) 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 (ELMORBD) 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−ELMO2RBD 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 DOCK2DHR2, 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.

Suggested Citation

  • 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, 2020. "Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17271-9
    DOI: 10.1038/s41467-020-17271-9
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    Cited by:

    1. Viviane Tran & Sarah Nahlé & Amélie Robert & Inès Desanlis & Ryan Killoran & Sophie Ehresmann & Marie-Pier Thibault & David Barford & Kodi S. Ravichandran & Martin Sauvageau & Matthew J. Smith & Marie, 2022. "Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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