Nature Structural & Molecular Biology11, 756 - 762 (2004)
Published online: 11 July 2004; | doi:10.1038/nsmb800
PH domain of ELMO functions in trans to regulate Rac activation via Dock180
Mingjian Lu1, Jason M Kinchen3, 4, Kent L Rossman5, Cynthia Grimsley1, 2, Colin deBakker1, Enrico Brugnera1, Annie-Carole Tosello-Trampont1, Lisa B Haney1, Doris Klingele3, John Sondek5, Michael O Hengartner3
& Kodi S Ravichandran1
1
Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
2
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
3
Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
4
Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA.
5
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Correspondence should be addressed to Kodi S Ravichandran ravi@virginia.edu
The members of the Dock180 superfamily of proteins are novel guanine nucleotide exchange factors (GEF) for Rho family GTPases and are linked to multiple biological processes from worms to mammals. ELMO is a critical regulator of Dock180, and the Dock180−ELMO complex functions as a bipartite GEF for Rac. We identified a mechanism wherein the PH domain of ELMO, by binding the Dock180−Rac complex in trans, stabilizes Rac in the nucleotide-free transition state. Mutagenesis studies reveal that this ELMO PH domain−dependent regulation is essential for the Dock180−ELMO complex to function in phagocytosis and cell migration. Genetic rescue studies in Caenorhabditis elegans using ELMO and its homolog CED-12 support the above observations in vivo. These data reveal a new mode of action of PH domains and a novel, evolutionarily conserved mechanism by which a bipartite GEF can activate Rac.
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