4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-17271-9

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Funding

  1. MRC Laboratory of Molecular Biology
  2. MRC [MC_UP_1201/6]
  3. Cancer Research UK [C576/A14109]
  4. Canadian Institutes for Health Research (CIHR)
  5. National Science and Engineering Council of Canada (NSERC)
  6. Fonds de recherche du Quebec - Sante (FRQS)
  7. Wellcome Trust
  8. MRC
  9. BBSRC
  10. MRC [MC_UP_1201/6] Funding Source: UKRI

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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 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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