PH domain of ELMO functions in trans to regulate Rac activation via Dock180.
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.
Lu
Mingjian
M
Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Kinchen
Jason M
JM
Rossman
Kent L
KL
Grimsley
Cynthia
C
deBakker
Colin
C
Brugnera
Enrico
E
Tosello-Trampont
Annie-Carole
AC
Haney
Lisa B
LB
Klingele
Doris
D
Sondek
John
J
Hengartner
Michael O
MO
Ravichandran
Kodi S
KS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D016296:Mutagenesis; D009154:Mutation; D010587:Phagocytosis; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013997:Time Factors; D019076:Transgenes; D020744:rac GTP-Binding Proteins / Q000737:chemistry*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C438369:CED-12 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D006160:Guanosine Triphosphate; D005982:Glutathione Transferase; D020744:rac GTP-Binding Proteins