Pechlivanis Markos, Ringel Rieke, Popkirova Boriana, Kuhlmann Juergen
Department of Structural Biology, Max-Planck-Institut für molekulare Physiologie, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Biochemistry. 2007 May 8;46(18):5341-8. doi: 10.1021/bi602353k. Epub 2007 Apr 17.
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.
癌蛋白Ras因其C末端脂质修饰而锚定在脂质膜上。广泛表达的Ras核苷酸交换因子hSOS1促进核苷酸交换，从而激活Ras。该反应通过正反馈回路增强，即活化的Ras与SOS的变构位点结合以增强鸟嘌呤核苷酸交换因子（GEF）活性。在此，我们展示了生化数据，表明有效促进hSOS1核苷酸交换需要活性位点结合和变构结合的N-Ras的异戊二烯化。我们的结果表明，变构反馈激活的异戊二烯敏感性由hSOS1的PH结构域介导。因此，Ras的法尼基化允许hSOS1即使与负载GDP的变构调节因子结合，以维持基础hSOS1活性。
