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

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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.