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MBC in Press, published online ahead of print September 3, 2008
Mol. Biol. Cell 10.1091/mbc.E08-04-0345

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Submitted on April 3, 2008
Revised on August 15, 2008
Accepted on August 22, 2008

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

David Komander,*{dagger}{ddagger} Manishha Patel,*{dagger} Mélanie Laurin,{sect} Nadine Fradet,{sect} Ariane Pelletier,{sect} David Barford,* and Jean-François Côté{sect}||¶

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

Monitoring Editor: Josephine C. Adams

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 Prorich 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. Keywords: DOCK180/ELMO1/Rac activation/PH domain/Cell migration

{dagger}These authors contributed equally to this work.

{ddagger}Present address: Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom.

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




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