Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.
Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.
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DOI：
10.3389/fmolb.2021.707439
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发表时间：
2021
影响因子：
5
通讯作者：
Sasaki AT
中科院分区：
文献类型：
--
作者：
Osaka N;Hirota Y;Ito D;Ikeda Y;Kamata R;Fujii Y;Chirasani VR;Campbell SL;Takeuchi K;Senda T;Sasaki AT
RAS是GTP酶RAS超家族的创始成员。这些小的21 kDa蛋白质作为分子开关，以启动参与各种细胞过程的信号级联，包括基因表达，细胞生长和分化。RAS被GTP负载激活，并在GTP水解为GDP时失活。鸟嘌呤核苷酸交换因子（GEF）和GTP酶激活蛋白（GAP）分别加速GTP的加载和水解。这些辅助蛋白通过保守的鸟嘌呤结合（G）结构域（由5个G基序组成）在调节RAS超家族小GT3的活性中起重要作用。开关区域位于G2和G3基序内或邻近G2和G3基序，并在GDP结合的“OFF”状态和GTP结合的“ON”状态之间经历动态构象变化。它们在识别调控因子（GEF和GAP）和效应物方面发挥着重要作用。G4和G5基序是本工作的重点，位于开关区域之外。这些基序负责识别GTP和GDP中的鸟嘌呤部分，并含有进行翻译后修饰的残基，这些残基是RAS调节的新机制的基础。G4和G5基序内的翻译后修饰通过增强内在鸟嘌呤核苷酸交换或损害GAP介导的下调而使GTP结合的“ON”状态增加，从而激活RAS。在这里，我们提供了一个全面的审查RAS G4和G5基序的翻译后修饰，并描述了这些修饰在RAS激活的作用，以及潜在的应用于癌症治疗。
RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) accelerate GTP loading and hydrolysis, respectively. These accessory proteins play a fundamental role in regulating activities of RAS superfamily small GTPase via a conserved guanine binding (G)-domain, which consists of five G motifs. The Switch regions lie within or proximal to the G2 and G3 motifs, and undergo dynamic conformational changes between the GDP-bound “OFF” state and GTP-bound “ON” state. They play an important role in the recognition of regulatory factors (GEFs and GAPs) and effectors. The G4 and G5 motifs are the focus of the present work and lie outside Switch regions. These motifs are responsible for the recognition of the guanine moiety in GTP and GDP, and contain residues that undergo post-translational modifications that underlie new mechanisms of RAS regulation. Post-translational modification within the G4 and G5 motifs activates RAS by populating the GTP-bound “ON” state, either through enhancement of intrinsic guanine nucleotide exchange or impairing GAP-mediated down-regulation. Here, we provide a comprehensive review of post-translational modifications in the RAS G4 and G5 motifs, and describe the role of these modifications in RAS activation as well as potential applications for cancer therapy.
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影响因子：
5.4
作者：
Ahearn I;Zhou M;Philips MR
通讯作者：
Philips MR
影响因子：
7.4
作者：
Davis, Michael F.;Vigil, Dom;Campbell, Sharon L.
通讯作者：
Campbell, Sharon L.
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
64.8
作者：
Canon, Jude;Rex, Karen;Lipford, J. Russell
通讯作者：
Lipford, J. Russell
DOI：
10.1042/bj20151227
发表时间：
2016-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Davies MJ
通讯作者：
Davies MJ