Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146, Roma, Italy.
Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146, Roma, Italy.
Redox Biol. 2019 Sep;26:101282. doi: 10.1016/j.redox.2019.101282. Epub 2019 Jul 25.
Reactive oxygen and nitrogen species (ROS and RNS, respectively) activate the redox-sensitive Ras small GTPases. The three canonical genes (HRAS, NRAS, and KRAS) are archetypes of the superfamily of small GTPases and are the most common oncogenes in human cancer. Oncogenic Ras is intimately linked to redox biology, mainly in the context of tumorigenesis. The Ras protein structure is highly conserved, especially in effector-binding regions. Ras small GTPases are redox-sensitive proteins thanks to the presence of the NKCD motif (Asn116-Lys 117-Cys118-Asp119). Notably, the ROS- and RNS-based oxidation of Cys118 affects protein stability, activity, and localization, and protein-protein interactions. Cys residues at positions 80, 181, 184, and 186 may also help modulate these actions. Moreover, oncogenic mutations of Gly12Cys and Gly13Cys may introduce additional oxidative centres and represent actionable drug targets. Here, the pathophysiological involvement of Cys-redox regulation of Ras proteins is reviewed in the context of cancer and heart and brain diseases.
活性氧和氮物种（ROS 和 RNS，分别）激活氧化还原敏感的 Ras 小 GTPases。三个典型基因（HRAS、NRAS 和 KRAS）是小 GTPases 超家族的原型，是人类癌症中最常见的致癌基因。致癌性 Ras 与氧化还原生物学密切相关，主要是在肿瘤发生的背景下。Ras 蛋白结构高度保守，特别是在效应子结合区域。Ras 小 GTPases 是氧化还原敏感的蛋白质，这要归功于 NKCD 基序（Asn116-Lys117-Cys118-Asp119）的存在。值得注意的是，Cys118 的 ROS 和 RNS 基氧化影响蛋白质稳定性、活性和定位以及蛋白质-蛋白质相互作用。位置 80、181、184 和 186 的 Cys 残基也可能有助于调节这些作用。此外，Gly12Cys 和 Gly13Cys 的致癌突变可能引入额外的氧化中心，并代表可操作的药物靶点。在这里，Ras 蛋白的 Cys 氧化还原调节的病理生理作用在癌症、心脏和大脑疾病的背景下进行了综述。
