The Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom.
School of Chemistry, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom.
Sci Rep. 2017 Nov 27;7(1):16338. doi: 10.1038/s41598-017-15997-z.
Large-scale characterisation of cysteine modification is enabling study of the physicochemical determinants of reactivity. We find that location of cysteine at the amino terminus of an α-helix, associated with activity in thioredoxins, is under-represented in human protein structures, perhaps indicative of selection against background reactivity. An amino-terminal helix location underpins the covalent linkage for one class of kinase inhibitors. Cysteine targets for S-palmitoylation, S-glutathionylation, and S-nitrosylation show little correlation with pKa values predicted from structures, although flanking sequences of S-palmitoylated sites are enriched in positively-charged amino acids, which could facilitate palmitoyl group transfer to substrate cysteine. A surprisingly large fraction of modified sites, across the three modifications, would be buried in native protein structure. Furthermore, modified cysteines are (on average) closer to lysine ubiquitinations than are unmodified cysteines, indicating that cysteine redox biology could be associated with protein degradation and degron recognition.
大规模的半胱氨酸修饰特征分析使研究反应的物理化学决定因素成为可能。我们发现，与硫氧还蛋白活性相关的半胱氨酸位于α-螺旋的氨基末端，在人类蛋白质结构中代表性不足，这可能表明存在针对背景反应性的选择。一个氨基末端螺旋位置为一类激酶抑制剂的共价键连接提供了基础。S-棕榈酰化、S-谷胱甘肽化和 S-亚硝化的半胱氨酸靶标与从结构预测的 pKa 值几乎没有相关性，尽管 S-棕榈酰化位点的侧翼序列富含带正电荷的氨基酸，这可以促进棕榈酰基转移到底物半胱氨酸上。三种修饰中，相当大一部分修饰位点在天然蛋白质结构中被掩盖。此外，与未修饰的半胱氨酸相比，修饰的半胱氨酸（平均）更接近赖氨酸泛素化，表明半胱氨酸氧化还原生物学可能与蛋白质降解和 degron 识别有关。
