Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS.
Growth factor receptors activate Ras by recruiting the nucleotide exchange factor son of sevenless (SOS) to the cell membrane, thereby triggering the production of GTP-loaded Ras. Crystallographic analyses of Ras bound to the catalytic module of SOS have led to the unexpected discovery of a highly conserved Ras binding site on SOS that is located distal to the active site and is specific for Ras.GTP. The crystal structures suggest that Ras.GTP stabilizes the active site of SOS allosterically, and we show that Ras.GTP forms ternary complexes with SOS(cat) in solution and increases significantly the rate of SOS(cat)-stimulated nucleotide release from Ras. These results demonstrate the existence of a positive feedback mechanism for the spatial and temporal regulation of Ras.
Margarit
S Mariana
SM
Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Sondermann
Holger
H
Hall
Brian E
BE
Nagar
Bhushan
B
Hoelz
Andre
A
Pirruccello
Michelle
M
Bar-Sagi
Dafna
D
Kuriyan
John
J
D020134:Catalytic Domain / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism*; D005057:Eukaryotic Cells / Q000378:metabolism*; D025461:Feedback, Physiological / Q000235:genetics*; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D009711:Nucleotides; D020664:Son of Sevenless Proteins; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins