Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.
Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.
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DOI：
10.1021/bi400679q
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发表时间：
2013-11-26
期刊：
影响因子：
2.9
通讯作者：
Heo, Jongyun
中科院分区：
文献类型：
--
作者：
Wey, Michael;Lee, Jungwoon;Jeong, Soon Seog;Kim, Jungho;Heo, Jongyun
Costello综合征与Harvey Ras（HRas）的p环或NKCD/SAK基序中残基的激活突变有关。已经鉴定了超过10种诱导Costello综合征的HRas突变体; G12 S HRas是其中最普遍的。然而，某些HRas p环突变也与以G12 V HRas为例的癌症形成有关。尽管存在这些关系，但HRas突变类型与疾病之间的特定联系仍无法定义，因为某些Costello综合征HRas p环突变，如G12 S HRas，也经常导致癌症。本研究建立了新的动力学参数为基础的方程，估计的GTP结合的活性形式的HRas突变蛋白的细胞级分的值。这样的计算区分了两种基本的动力学机制，即在细胞中填充GTP结合形式的Ras。(i)通过HRas突变介导的Ras内在动力学特征的扰动增加GTP结合Ras。这产生了广泛的GTP结合形式的HRas群体，其通常引起Costello综合征。HRas突变体谱的上端，如G12 S HRas所例示的，也可以导致癌症。(ii)GTP结合Ras的增加是因为HRas突变干扰了p120 GAP对Ras的作用。这导致产生了一个显着的高人口的唯一的GTP结合形式的HRas只连接到癌症的形成。HRas突变体G12 V属于这一类。
Costello syndrome is linked to activating mutations of a residue in the p-loop or the NKCD/SAK motifs of Harvey Ras (HRas). More than 10 HRas mutants that induce Costello syndrome have been identified; G12S HRas is the most prevalent of these. However, certain HRas p-loop mutations also are linked to cancer formation that are exemplified with G12V HRas. Despite these relations, specific links between types of HRas mutations and diseases evade definition because some Costello syndrome HRas p-loop mutations, such as G12S HRas, also often cause cancer. This study established novel kinetic parameter-based equations that estimate the value of the cellular fractions of the GTP-bound active form of HRas mutant proteins. Such calculations differentiate between two basic kinetic mechanisms that populate the GTP-bound form of Ras in cells. (i) The increase in GTP-bound Ras by the HRas mutation-mediated perturbation of the intrinsic kinetic characteristics of Ras. This generates a broad spectrum of the population of the GTP-bound form of HRas that typically causes Costello syndrome. The upper end of this spectrum of HRas mutants, as exemplified by G12S HRas, can also cause cancer. (ii) The increase in GTP-bound Ras because the HRas mutations perturb the p120GAP action on Ras. This causes production of a significantly high population of the only GTP-bound form of HRas linked merely to cancer formation. The HRas mutant G12V belongs to this category.
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