QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 11, 4837-4851, November 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-04-0345v1 19/11/4837    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in Mol. Biol. Cell Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Komander, D. Articles by Côté, J.-F. Search for Related Content PubMed PubMed Citation Articles by Komander, D. Articles by Côté, J.-F.

An -Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and Is Critical in Rac Signaling

David Komander^*,,, Manishha Patel^,, Mélanie Laurin, Nadine Fradet, Ariane Pelletier, David Barford^*, and Jean-François Côté^,||,¶

*Section of Structural Biology, Chester Beatty Laboratories, Institute of Cancer Research, London SW3 6JB, United Kingdom; Institut de Recherches Cliniques de Montréal, Montréal QC, Canada H2W 1R7; ^||Faculté de Médecine, Université de Montréal; Montréal, QC, Canada H3C 3J7; and ^¶Division of Experimental Medicine, McGill University, Montréal, QC, Canada H3A 1A3

Submitted April 3, 2008; Revised August 15, 2008; Accepted August 22, 2008
Monitoring Editor: Josephine C. Adams

InCytes from MBC

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 -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.

These authors contributed equally to this work.

Present address: Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.

Address correspondence to: Jean-François Côté (jean-francois.cote{at}ircm.qc.ca)

Abbreviations used: DHR-2, DOCK homology region 2; GEF, guanine nucleotide exchange factor; PH, pleckstrin homology; pro-rich, proline-rich.

Related articles in Mol. Biol. Cell:

InCytes from MBC, November 2008

Mol. Biol. Cell 2008 19: 4545. [PDF]  

This article has been cited by other articles:

				J. Yang, Z. Zhang, S. M. Roe, C. J. Marshall, and D. Barford Activation of Rho GTPases by DOCK Exchange Factors Is Mediated by a Nucleotide Sensor Science, September 11, 2009; 325(5946): 1398 - 1402. [Abstract] [Full Text] [PDF]

				M. A. Sanders, D. Ampasala, and M. D. Basson DOCK5 and DOCK1 Regulate Caco-2 Intestinal Epithelial Cell Spreading and Migration on Collagen IV J. Biol. Chem., January 2, 2009; 284(1): 27 - 35. [Abstract] [Full Text] [PDF]