Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression
Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression
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DOI：
10.1002/(sici)1096-9896(199903)187:4
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发表时间：
1999-03-01
影响因子：
7.3
通讯作者：
Birnie, GD
中科院分区：
文献类型：
--
作者：
Al-Mulla, F;Milner-White, EJ;Birnie, GD
最近的证据表明，密码子12缬氨酸-甘氨酸（G12 V）突变Ki-Ras蛋白与结直肠癌的更高阶段和更高的致死率相关，而密码子12缬氨酸-甘氨酸（G12 D）Ras突变没有显示出这种关联。几个观察结果可能与这种现象有关。首先，G12 Y Ras的GTdR活性是G12 D Ras的四分之一，是野生型（WT）Pas的十分之一。第二，GTP类似物GppNp与G12 D Ras的结合比其与G12 V或WT Ras的结合弱8倍，并且晶体结构表明G12 D Asp-12侧链的羧酸酯基团与结合的核苷酸的γ磷酸之间的静电排斥可以使GTP与G12 D Ras的结合甚至比GppNp的结合更弱，有人提出，这种对GTP亲和力的降低允许G12 D Pas从致癌的GTP结合状态中逃逸，而GTP与G12 V突变体Ras紧密结合产生更持久的、潜在致癌的信号。结构比较还表明，G12 D和G12 V Pas的开关I（效应器）区域之间的差异可以改变与下游信号传导分子如Raf-I、神经纤维蛋白和磷脂酰肌醇3-羟基激酶的相互作用。G12 D和G12 V突变体Ras蛋白之间的其它差异包括GT3活化蛋白GAP对G12 V的亲和力低于对G12 D或WT Ras的亲和力;但是，由于G12 D和G12 VPas两者对GAP结合引起的GT3活化都是难治的，因此这可能不太重要。这些研究补充了实验数据，表明这些Ras突变在体外和体内的作用不同，最近的数据表明结直肠癌和其他肿瘤中uas突变的异质性，使得密码子12 Pas突变在致癌潜力和预后意义上不同是合理的。版权所有（C）1999约翰威利父子有限公司。
Recent evidence associates the codon 12 valine-for-glycine (G12V) mutant Ki-Ras protein with higher stage and increased lethality of colorectal carcinomas, while the codon 12 aspartate-far-glycine (G12D) Ras mutation shows no such association. Several observations may be relevant to this phenomenon, First, GTPase activity of G12Y Ras is one-quarter that of G12D Ras and one-tenth that of wild-type (WT) Pas. Second, binding of the GTP analogue GppNp to G12D Ras is 8-fold weaker than its binding to G12V or WT Ras and crystal structures indicate that electrostatic repulsion between the carboxylate group of the G12D Asp-12 side-chain and the gamma phosphate of the bound nucleotide may make GTP binding to G12D Pas weaker even than that of GppNp, It is proposed that this lowering of affinity for GTP allows G12D Pas an escape From the oncogenic GTP-bound state, whereas GTP tightly bound to G12V mutant Ras generates a more persistent, potentially oncogenic, signal. Structural comparisons also suggest that differences between the Switch I (effector) region of G12D and G12V Pas could modify interactions with downstream signalling molecules such as Raf-l, neurofibromin, and phosphatidylinositol 3-hydroxy-kinase. Other differences between the G12D and G12V mutant Ras proteins include a lower affinity of the GTPase activating protein GAP for G12V than for G12D or WT Ras; but, as both G12D and G12V Pas are refractory to GTPase activation by GAP binding, this may be less significant, These studies complement experimental data showing that such Ras mutations differ in their effects in vitro and in vivo and, with recent data indicating heterogeneity of uas mutation in colorectal carcinomas and other tumours, make it plausible that codon 12 Pas mutations differ in carcinogenic potential and prognostic significance. Copyright (C) 1999 John Wiley & Sons, Ltd.