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, David Barford

Nature communications 2020 Jul 10

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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 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.

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. Structure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state. Nature communications. 2020 Jul 10;11(1):3464