Document Detail


An alpha-helical extension of the ELMO1 pleckstrin homology domain mediates direct interaction to DOCK180 and is critical in Rac signaling.
MedLine Citation:
PMID:  18768751     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The mammalian DOCK180 protein belongs to an evolutionarily conserved protein family, which together with ELMO proteins, is essential for activation of Rac GTPase-dependent biological processes. Here, we have analyzed the DOCK180-ELMO1 interaction, and map direct interaction interfaces to the N-terminal 200 amino acids of DOCK180, and to the C-terminal 200 amino acids of ELMO1, comprising the ELMO1 PH domain. Structural and biochemical analysis of this PH domain reveals that it is incapable of phospholipid binding, but instead structurally resembles FERM domains. Moreover, the structure revealed an N-terminal amphiphatic alpha-helix, and point mutants of invariant hydrophobic residues in this helix disrupt ELMO1-DOCK180 complex formation. A secondary interaction between ELMO1 and DOCK180 is conferred by the DOCK180 SH3 domain and proline-rich motifs at the ELMO1 C-terminus. Mutation of both DOCK180-interaction sites on ELMO1 is required to disrupt the DOCK180-ELMO1 complex. Significantly, although this does not affect DOCK180 GEF activity toward Rac in vivo, Rac signaling is impaired, implying additional roles for ELMO in mediating intracellular Rac signaling.
Authors:
David Komander; Manishha Patel; Mélanie Laurin; Nadine Fradet; Ariane Pelletier; David Barford; Jean-François Côté
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-03
Journal Detail:
Title:  Molecular biology of the cell     Volume:  19     ISSN:  1939-4586     ISO Abbreviation:  Mol. Biol. Cell     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-10-29     Completed Date:  2008-12-24     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  9201390     Medline TA:  Mol Biol Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4837-51     Citation Subset:  IM    
Affiliation:
Section of Structural Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
PDB/2VSZ
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / chemistry*,  metabolism*
Amino Acid Motifs
Amino Acid Sequence
Animals
Binding Sites
Cell Line
Conserved Sequence
Enzyme Activation
Evolution, Molecular
Humans
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Sequence Data
Phosphatidylinositols / metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Signal Transduction*
Structure-Activity Relationship
Surface Properties
rac GTP-Binding Proteins / chemistry,  metabolism*
Grant Support
ID/Acronym/Agency:
77591//Canadian Institutes of Health Research; //Cancer Research UK
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/DOCK1 protein, human; 0/ELMO1 protein, human; 0/Phosphatidylinositols; EC 3.6.5.2/rac GTP-Binding Proteins
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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