Scientific article
OA Policy
English

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

Published inNature communications, vol. 11, no. 1
Publication date2020-07-10
First online date2020-07-10
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 (DOCK DHR2 ) and membrane-associated (DOCK DHR1 ) 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 (ELMO RBD ) 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−ELMO2 RBD 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.

Funding
  • UK Research and Innovation - Mechanism of chromosome segregation in mitosis [MC_UP_1201/6]
  • Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada -
  • Cancer Research UK - [C576/A14109]
  • Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre -
  • Biotechnology and Biological Sciences Research Council -
  • CIHR -
  • Wellcome Trust -
Citation (ISO format)
CHANG, Leifu et al. Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state. In: Nature communications, 2020, vol. 11, n° 1. doi: 10.1038/s41467-020-17271-9
Main files (1)
Article (Published version)
Identifiers
Additional URL for this publicationhttps://www.nature.com/articles/s41467-020-17271-9
Journal ISSN2041-1723
49views
29downloads

Technical informations

Creation05/12/2023 14:03:22
First validation05/12/2023 14:09:05
Update time05/12/2023 14:09:05
Status update05/12/2023 14:09:05
Last indexation01/11/2024 07:57:59
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack