Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state
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Killoran, Ryan C.
Nature Publishing Group UK
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Chang, L., Yang, J., Jo, C. H., Boland, A., Zhang, Z., McLaughlin, S. H., Abu-Thuraia, A., et al. (2020). Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state. Nature Communications, 11 (1)https://doi.org/10.1038/s41467-020-17271-9
Funder: Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre); doi: https://doi.org/10.13039/501100007202
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: https://doi.org/10.13039/501100002790
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.
Article, /631/45, /631/45/603, /631/45/612, /631/80, /631/80/79, /101, /101/28, /9, /82/83, article
RCUK | Medical Research Council (MRC) (MC_UP_1201/6)
Cancer Research UK (CRUK) (C576/A14109)
External DOI: https://doi.org/10.1038/s41467-020-17271-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/307839