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

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 and David Barford ()
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Leifu Chang: MRC Laboratory of Molecular Biology
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
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
Jean-Francois Côté: Montreal Institute of Clinical Research (IRCM)
David Barford: MRC Laboratory of Molecular Biology

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17271-9

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