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

Nat Commun. 2020 Jul 10;11(1):3464. doi: 10.1038/s41467-020-17271-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Calorimetry
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Kinetics
  • Microscopy, Electron
  • Phosphorylation
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • DOCK2 protein, human
  • ELMO1 protein, human
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • RHOG protein, human
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins