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Crystal structures of acetylated HRas K104 mimic K104Q and mutant K104A suggest unique role of K104 in interlobe communication across HRas

Ras GTPases belong to a subfamily of signal transduction switches found in the Ras superfamily. Three isoforms of Ras (H‐, K‐, and N‐Ras) are expressed to regulate cellular proliferation, growth, and apoptosis. Unregulated activity of these proteins is closely related to disease, particularly the growth of tumors.1 The GTP/GDP cycle is a common regulatory feature of signaling output across GTPases. Exchange of GDP for GTP within the Ras active site results in an active signaling cascade. GAPs accelerate the hydrolysis of GTP to GDP, turning off the signal. In addition to exchange factors and activating proteins, the Ras GTPase cycle is also controlled by post‐translational modifications. An acetylation mimic (K104Q) in KRas G12V has been shown to negate oncogenic growth of the double mutant cell lines. However, KRas K104A/G12V does not reduce the oncogenicity of the cell line.2 The purpose of this study is to investigate the structural‐functional implications of K104Q and K104A mutations in HRas through X‐ray crystallography and to obtain their intrinsic hydrolysis rates through kinetic experiments with γ‐32P‐GTP. These data show a novel hydrogen‐bonding network present in K104Q, but not WT or K104A HRas. Intrinsic hydrolysis of GTP to GDP is significantly impaired in HRas K104Q, but is not affected by a K104A mutation. The unique network may control helix 5 motility in HRas, resulting in a lower intrinsic hydrolysis rate. Connectivity from K104Q towards helix 5 passes through a region of amino acids that are different between the H‐, K‐, and N‐ Ras isoforms. This suggests that Ras acetylation of K104 may affect the function of the isoforms in subtly different ways.