Gray Vanessa E, Liu Li, Nirankari Ronika, Hornbeck Peter V, Kumar Sudhir
Center for Evolutionary Medicine and Informatics, Biodesign Institute, Arizona State University.
Cell Signaling Technology, Danvers, MA.
Mol Biol Evol. 2014 Jul;31(7):1641-5. doi: 10.1093/molbev/msu137. Epub 2014 Apr 16.
Posttranslational modifications (PTMs) regulate molecular structures and functions of proteins by covalently binding to amino acids. Hundreds of thousands of PTMs have been reported for the human proteome, with multiple PTMs known to affect tens of thousands of lysine (K) residues. Our molecular evolutionary analyses show that K residues with multiple PTMs exhibit greater conservation than those with a single PTM, but the difference is rather small. In contrast, short-term evolutionary trends revealed in an analysis of human population variation exhibited a much larger difference. Lysine residues with three PTMs show 1.8-fold enrichment of Mendelian disease-associated variants when compared with K residues with two PTMs, with the latter showing 1.7-fold enrichment of these variants when compared with the K residues with one PTM. Rare polymorphisms in humans show a similar trend, which suggests much greater negative selection against mutations of K residues with multiple PTMs within population. Conversely, common polymorphisms are overabundant at unmodified K residues and at K residues with fewer PTMs. The observed difference between inter- and intraspecies patterns of purifying selection on residues with PTMs suggests extensive species-specific drifting of PTM positions. These results suggest that the functionality of a protein is likely conserved, without necessarily conserving the PTM positions over evolutionary time.
翻译后修饰（PTMs）通过与氨基酸共价结合来调节蛋白质的分子结构和功能。据报道，人类蛋白质组中有数十万种翻译后修饰，已知多种翻译后修饰会影响数万个赖氨酸（K）残基。我们的分子进化分析表明，具有多种翻译后修饰的赖氨酸残基比具有单一翻译后修饰的赖氨酸残基表现出更高的保守性，但差异相当小。相比之下，在对人类群体变异的分析中揭示的短期进化趋势显示出更大的差异。与具有两种翻译后修饰的赖氨酸残基相比，具有三种翻译后修饰的赖氨酸残基显示孟德尔疾病相关变异的富集倍数为1.8倍，而与具有一种翻译后修饰的赖氨酸残基相比，后者显示这些变异的富集倍数为1.7倍。人类中的罕见多态性显示出类似的趋势，这表明在群体中对具有多种翻译后修饰的赖氨酸残基的突变存在更大的负选择。相反，常见多态性在未修饰的赖氨酸残基和具有较少翻译后修饰的赖氨酸残基处过度丰富。在具有翻译后修饰的残基上，种间和种内纯化选择模式之间观察到的差异表明翻译后修饰位置存在广泛的物种特异性漂移。这些结果表明，蛋白质的功能可能是保守的，而不一定在进化时间内保守翻译后修饰的位置。
