Kapell Sebastian, Jakobsson Magnus E
National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
Department of Immunotechnology, Lund University, Lund, Sweden.
NAR Genom Bioinform. 2021 May 22;3(2):lqab045. doi: 10.1093/nargab/lqab045. eCollection 2021 Jun.
Methylation can occur on histidine, lysine and arginine residues in proteins and often serves a regulatory function. Histidine methylation has recently attracted attention through the discovery of the human histidine methyltransferase enzymes SETD3 and METTL9. There are currently no methods to enrich histidine methylated peptides for mass spectrometry analysis and large-scale studies of the modification are hitherto absent. Here, we query ultra-comprehensive human proteome datasets to generate a resource of histidine methylation sites. In HeLa cells alone, we report 299 histidine methylation sites as well as 895 lysine methylation events. We use this resource to explore the frequency, localization, targeted domains, protein types and sequence requirements of histidine methylation and benchmark all analyses to methylation events on lysine and arginine. Our results demonstrate that histidine methylation is widespread in human cells and tissues and that the modification is over-represented in regions of mono-spaced histidine repeats. We also report colocalization of the modification with functionally important phosphorylation sites and disease associated mutations to identify regions of likely regulatory and functional importance. Taken together, we here report a system level analysis of human histidine methylation and our results represent a comprehensive resource enabling targeted studies of individual histidine methylation events.
甲基化可发生在蛋白质的组氨酸、赖氨酸和精氨酸残基上，且常发挥调节功能。组氨酸甲基化最近因人类组氨酸甲基转移酶SETD3和METTL9的发现而受到关注。目前尚无用于富集组氨酸甲基化肽以进行质谱分析的方法，并且迄今为止缺乏对该修饰的大规模研究。在此，我们查询超全面的人类蛋白质组数据集以生成组氨酸甲基化位点资源。仅在HeLa细胞中，我们就报告了299个组氨酸甲基化位点以及895个赖氨酸甲基化事件。我们利用这一资源来探索组氨酸甲基化的频率、定位、靶向结构域、蛋白质类型和序列要求，并将所有分析与赖氨酸和精氨酸上的甲基化事件进行基准比较。我们的结果表明，组氨酸甲基化在人类细胞和组织中广泛存在，并且该修饰在单间隔组氨酸重复区域中过度富集。我们还报告了该修饰与功能重要的磷酸化位点和疾病相关突变的共定位，以确定可能具有调节和功能重要性的区域。综上所述，我们在此报告了对人类组氨酸甲基化的系统水平分析，我们的结果代表了一个全面的资源，可用于对单个组氨酸甲基化事件进行靶向研究。
