Computational analyses of the conservation, competition and crosstalk of lysine-based post-translational modifications (PTMs)

项目摘要（最多4000个字符，包括空格/回车）-来自原始提案细胞通过所有生命形式中蛋白质的翻译后修饰（PTM）快速信号传导来响应压力。PTM包括通过化学基团（例如磷酸化、乙酰化、甲基化，仅举几例）对特定氨基酸的侧链进行可逆修饰以及添加/去除小蛋白（例如泛素和SUMO）。这些PTM具有多种作用，包括激活或抑制其他蛋白质，包括信号传导链，例如通过激酶磷酸化其他激酶，刺激蛋白质降解（泛素化的主要作用）或改变蛋白质的相互作用网络（SUMO化）。PTM参与了几乎所有类型的生物过程，因此也参与了多种疾病，包括癌症、神经变性、感染性和自身免疫性疾病。最常见的修饰氨基酸是赖氨酸，这意味着不同修饰类型之间可以相互作用，从而实现响应的微调，例如通过竞争泛素的一个赖氨酸残基在降解或激活之间快速切换，乙酰化或SUMO化，或邻近赖氨酸之间的串扰。许多PTM位点是保守的，这意味着在模型物种中的发现可以应用于人类（例如用于研究疾病），并且新的理解可以帮助揭示“生命规则”（BBSRC主题）。在这个项目中，我们将与英国/美国资助的PTMeXchange财团合作，由主要主管领导，为人类，小鼠和其他模型生物创建高质量的PTM“构建”-目标1。构建将通过重新处理关于赖氨酸泛素化、乙酰化和SUMO化的公开可用质谱（MS）数据集来创建，结果将保存在世界领先的知识库UniProtKB中。接下来，我们将使用统计方法来发现不同赖氨酸修饰之间的相互作用或竞争的规则，即存在竞争或串扰的蛋白质组或途径，并对负责的酶进行预测-目标2。最后，我们将探索这些关系的进化保守性，以提高我们对位点特异性规则的理解，与联合进化压力下共同进化酶对的出现有关-目标3。

Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Cells respond to stress via rapid signalling through post-translational modifications (PTMs) of proteins in all forms of life. PTMs include reversible modification of the side chains of specific amino acids by chemical groups (e.g. phosphorylation, acetylation, methylation to name just a few) and addition/removal of a small protein (e.g. ubiquitin and SUMO). These PTMs have a multitude of roles, including activating or repressing other proteins, including signalling chains e.g. via kinases phosphorylating other kinases, stimulating protein degradation (the major role of ubiquitination) or altering the interaction network of the protein (SUMOylation). PTMs have been implicated in almost all types of biological processes and as a consequence, also in multiple diseases, including cancers, neurodegeneration, infectious and autoimmune diseases.The most commonly modified amino acid is lysine, meaning that there can be interplay between different modification types, enabling fine-tuning of responses e.g. fast switching between degradation or activation by competition at one lysine residue for ubiquitin, acetylation or SUMOylation, or crosstalk between nearby lysines. Many PTM sites are conserved, meaning discoveries in a model species can be applied to humans (e.g. for studying diseases), and that new understanding can help to uncover "Rules of Life" (BBSRC theme).In this project, working with UK/US funded PTMeXchange consortium led by the primary supervisor, we will create high-quality PTM "builds" for human, mouse and other model organisms - objective 1. Builds will be created by re-processing publicly available mass spectrometry (MS) data sets on lysine ubiquitination, acetylation and SUMOylation, and results will be deposited in world leading knowledgebase UniProtKB. Next, we will use statistical methods to discover the rules governing interactions or competition between different lysine modifications i.e. groups of proteins or pathways where competition or crosstalk exists and make predictions about the enzymes responsible - objective 2. Finally, we will explore the evolutionary conservation of these relationships to improve our understanding of site-specificity rules, linked to the emergence of pairs of co-evolving enzymes under joint evolutionary pressures - objective 3.