Department of Chemistry, University at Buffalo, State University of New York, 515 Natural Sciences Complex, Buffalo, NY, 14260, USA.
Redox Biol. 2021 May;41:101934. doi: 10.1016/j.redox.2021.101934. Epub 2021 Mar 5.
The Src Family Kinases (SFKs) are pivotal regulators of cellular signal transduction and highly sought-after targets in drug discovery. Their actions within cells are controlled by alterations in protein phosphorylation that switch the SFKs from autoinhibited to active states. The SFKs are also well recognized to contain redox-active cysteine residues where oxidation of certain residues directly contribute to kinase function. To more completely understand the factors that influence cysteine oxidation within the SFKs, a review is presented of the local structural environments surrounding SFK cysteine residues compared to their quantified oxidation in vivo from the Oximouse database. Generally, cysteine local structure and degree of redox sensitivity vary with respect to sequence conservation. Cysteine residues found in conserved positions are more mildly redox-active as they are found in hydrophobic environments and not fully exposed to solvent. Non-conserved redox-active cysteines are generally the most reactive with direct solvent access and/or in hydrophilic environments. Results from this analysis motivate future efforts to conduct comprehensive proteome-wide analysis of redox-sensitivity, conservation, and local structural environments of proteins containing reactive cysteine residues.
Src 家族激酶 (SFKs) 是细胞信号转导的关键调节因子，也是药物发现中备受关注的靶点。它们在细胞内的作用受到蛋白质磷酸化的改变控制，这种改变将 SFKs 从自动抑制状态转变为激活状态。SFKs 还被广泛认为含有氧化还原活性半胱氨酸残基，其中某些残基的氧化直接促进激酶功能。为了更全面地了解影响 SFKs 中半胱氨酸氧化的因素，对 SFK 半胱氨酸残基周围的局部结构环境与 Oximouse 数据库中体内定量氧化进行了综述。通常，半胱氨酸局部结构和氧化还原敏感性随序列保守性而变化。在保守位置发现的半胱氨酸残基具有较低的氧化还原活性，因为它们位于疏水环境中，没有完全暴露于溶剂中。非保守的氧化还原活性半胱氨酸通常最具反应性，具有直接的溶剂接触和/或亲水环境。该分析的结果促使人们未来努力对含有反应性半胱氨酸残基的蛋白质进行全面的蛋白质组范围内的氧化还原敏感性、保守性和局部结构环境的分析。
