10.1021/bi602353k.s002 Markos Pechlivanis Markos Pechlivanis Rieke Ringel Rieke Ringel Boriana Popkirova Boriana Popkirova Juergen Kuhlmann Juergen Kuhlmann Prenylation of Ras Facilitates hSOS1-Promoted Nucleotide Exchange, upon Ras Binding to the Regulatory Site<sup>†</sup> American Chemical Society 2007 Ras Binding prenyl sensitivity hSOS 1 hSOS 1. Farnesylation GEF activity Ras activation feedback loop nucleotide exchange PH domain lipid membranes allosteric site 2007-05-08 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Prenylation_of_Ras_Facilitates_hSOS1_Promoted_Nucleotide_Exchange_upon_Ras_Binding_to_the_Regulatory_Site_sup_sup_/3008902 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.