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Mechanism of intrinsic hydrolysis in Ras and the effect of Raf on oncogenic Ras mutants

The Ras GTPase and its effector Raf are key mediators of the Raf/MEK/ERK signal transduction pathway, which plays a central role in cell growth and malignant transformation. While it is well accepted that signaling through the Ras/Raf interaction is critical in the development of many cancers, most studies to date have focused on the properties of the individual components of this complex. Thus, the biochemical properties of Ras and its oncogenic mutants have been well characterized in vitro in the absence of Raf and numerous structures of wild type and oncogenic Ras mutants have been used to study the possible mechanisms through which Ras becomes defective in its ability to hydrolyze GTP. We show that in the context of the Ras/Raf‐RBD‐CRD complex the highly oncogenic mutant RasQ61L is unable to hydrolyze GTP and that the high transformation efficiency in RasQ61L is correlated with an anti‐catalytic conformation of the active site in this and other highly transforming mutants. We propose a new mechanism through which intrinsic hydrolysis occurs in Ras and explain the structural features that render the RasQ61L mutant a severely impaired enzyme in the presence of Raf. We also present crystal structures supporting a role for Gln61 in our proposed mechanism and show how the G12V mutant disrupts this structure while in the non‐transforming G12P mutant it is well tolerated.