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TitleStructure of the DOCK2-ELMO1 complex provides insights into regulation of the auto-inhibited state.
Journal, issue, pagesNat Commun, Vol. 11, Issue 1, Page 3464, Year 2020
Publish dateJul 10, 2020
AuthorsLeifu 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 /
PubMed AbstractDOCK (dedicator of cytokinesis) proteins are multidomain guanine nucleotide exchange factors (GEFs) for RHO GTPases that regulate intracellular actin dynamics. DOCK proteins share catalytic (DOCK) ...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) and membrane-associated (DOCK) 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) 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 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, 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.
External linksNat Commun / PubMed:32651375 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.4 - 5.5 Å
Structure data

EMDB-10497, PDB-6tgb:
CryoEM structure of the binary DOCK2-ELMO1 complex
Method: EM (single particle) / Resolution: 5.5 Å

EMDB-10498: CryoEM structure of the ternary DOCK2-ELMO1-RAC1 complex
PDB-6tgc: CryoEM structure of the ternary DOCK2-ELMO1-RAC1 complex.
Method: EM (single particle) / Resolution: 4.1 Å

PDB-6uka:
Crystal structure of RHOG and ELMO complex
Method: X-RAY DIFFRACTION / Resolution: 2.4 Å

Chemicals

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM / 5'-Guanylyl imidodiphosphate

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / guanine nucleotide exchange factor / cytoskeleton / actin / cryoEM / RHOG / ELMO / RBD / complex / CELL ADHESION

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