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

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Chang, Leifu 
Yang, Jing 


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.


Funder: Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre); doi:

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi:


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

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Nat Commun

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Springer Science and Business Media LLC
RCUK | Medical Research Council (MRC) (MC_UP_1201/6)
Cancer Research UK (CRUK) (C576/A14109)