Prenylation of Ras facilitates hSOS1-promoted nucleotide exchange, upon Ras binding to the regulatory site.
The oncoprotein Ras is anchored in lipid membranes due to its C-terminal lipid modification. The ubiquitously expressed Ras nucleotide exchange-factor hSOS1 promotes nucleotide exchange and thus Ras activation. This reaction is enhanced by a positive feedback loop whereby activated Ras binds to an allosteric site of SOS to enhance GEF activity. Here we present biochemical data showing that prenylation of both active site bound and allosterically bound N-Ras is required for efficient hSOS1-promoted nucleotide exchange. Our results indicate that prenyl sensitivity of the allosteric feedback-activation is mediated by the PH domain of hSOS1. Farnesylation of Ras thereby allows hSOS1 to bind even GDP-loaded allosteric regulator to maintain basal hSOS1-activity.
Pechlivanis
Markos
M
Department of Structural Biology, Max-Planck-Institut für molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Ringel
Rieke
R
Popkirova
Boriana
B
Kuhlmann
Juergen
J
D000495:Allosteric Site; D001798:Blood Proteins / Q000378:metabolism / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D017368:Protein Prenylation / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040681:Structural Homology, Protein; D018631:ras Proteins / Q000378:metabolism* / Q000502:physiology
D001798:Blood Proteins; D020662:Guanine Nucleotide Exchange Factors; D010446:Peptide Fragments; D010750:Phosphoproteins; D020837:SOS1 Protein; C039077:platelet protein P47; D018631:ras Proteins