Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression.

摘要: Recent evidence associates the codon 12 valine-for-glycine (G12V) mutant Ki-Ras protein with higher stage and increased lethality of colorectal carcinomas, while aspartate-for-glycine (G12D) Ras mutation shows no such association. Several observations may be relevant to this phenomenon. First, GTPase activity G12V is one-quarter that G12D one-tenth wild-type (WT) Ras. Second, binding GTP analogue GppNp 8-fold weaker than its or WT crystal structures indicate electrostatic repulsion between carboxylate group Asp-12 side-chain γ phosphate bound nucleotide make even GppNp. It proposed lowering affinity for allows an escape from oncogenic GTP-bound state, whereas tightly generates a more persistent, potentially oncogenic, signal. Structural comparisons also suggest differences Switch I (effector) region could modify interactions downstream signalling molecules as Raf-1, neurofibromin, phosphatidylinositol 3-hydroxy-kinase. Other proteins include lower activating GAP Ras; but, both are refractory activation by binding, less significant. These studies complement experimental data showing mutations differ in their effects vitro vivo and, recent indicating heterogeneity ras carcinomas other tumours, it plausible carcinogenic potential prognostic significance. Copyright © 1999 John Wiley & Sons, Ltd.