Computational Identification And Functional Analysis Of Lysine Post-translational Modification Sites

With the completion of genetic engineering, post-genomic era means that the direction of the life of the study will move to new areas to more reactive functional proteomics. The rapid development of high-throughput experimental technologies such as functional proteomics research also provides new opportunities and challenges to promot the advancement of research in this field. As a common occurrence in the body mechanism, protein-translational modifications plays a very important role in the regulation of various physiological processes and functions. Although the high-throughput biological technology has made tremendous achievements in recognition of post-translational modification sites. But for the cost and labor considerations, there are still significant limitations. And it is also not ideal for exploring a deeper level in the relationship between structure and function. Therefore, the development of an accurate and efficient method of theoretical calculation after identification and analysis of protein post-translational modification owns very important significance. Based on the surrounding environment analysis such as the sequence of biochemical, structural and evolutionary conservation of various modifications to, we not only build a more modified sites forecasting tools, but also explored the potential impact of amino acid mutations to modified sites from the perspective of genetic variation and further related diseases that modified sites relevant. The main work is summarized as follows1. Protein function has been observed to rely on select essential sites instead of requiring all sites to be indispensable. Small ubiquitin-related modifier(SUMO) conjugation or SUMOylation, which is a highly dynamic reversible process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified, has shown to be especially valuable in cellular biology. Motivated by the significance of SUMO conjugation in biological processes, we report here on the first exploratory assessment whether SUMOylation related genetic variability impacts protein functions as well as the occurrence of diseases related to SUMO. Here, we defined the SUMOAMVR as SUMOylation related amino acid variations that affect SUMOylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs. We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system. More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine SUMOylation sites are more likely to cause diseases. It can be anticipated that our method can provide more instructive guidance to identify the mechanisms of genetic diseases.2. Lysine succinylation orchestrates a variety of biological processes. Annotation of succinylation in proteomes is the first-crucial step to decipher physiological roles of succinylation implicated in the pathological processes. In this work, we developed a novel succinylation site online prediction tool, called SuccFind, which is constructed to predict the lysine succinylation sites based on two major categories of characteristics: sequence-derived features and evolutionary-derived information of sequence and via an enhanced feature strategy for further optimizations. The assessment results obtained from cross-validation suggest that SuccFind can provide more instructive guidance for further experimental investigation of protein succinylation. It is our desire to build an open platform which could provide more useful guidance for experimental workers of identification of succinylation sites. The web service of SuccFind is freely available at: http://bioinfo.ncu.edu.cn/SuccFind.aspx. The improved succinylation prediction system will be done when the new succinylation sites data become available. We anticipate that the SuccFind will be a powerful and complementary tool for further experimental investigation of protein succinylation.3. Recent studies have indicated that post-translational modifications(PTMs) occurred at lysine(PLMs) synergistically orchestrate specific biological processes in cell physiology and pathology by crosstalks. However, the preference of the crosstalk among different PLMs and their function remain to be systematically characterized. To this end, the in situ crosstalk at the same positions among three lysine modifications including succinylation, SUMOyaltion and acetylation were systematically deciphered in a site-specific manner. From the results, we detected that the in situ crosstalk between succinylation and SUMOyaltion is under-represented, whereas both succinylation and SUMOyaltion prefer to co-occupy with acetylation at same lysine and participate in distinct biological processes and functions as well as co-regulates a tight functional cluster of heavily modified and dynamic proteins. Further analyses of subcellular localization and biochemical environment revealed these different lysine modifications prefer to co-occur at distinct subcellular compartment and structural positions. Short-term evolutionary analysis declared that there is no additional natural selection on significantly co-occupied crosstalk sites. But interestingly, genetic variations at adjacent positions of modified sites might impact central sites to some extent and played some role in human diseases. Phylogenetic classification also revealed genes with co-occupied lysine crosstalks are more likely comprising higher evolutionary similarity and possess a tendency to cluster in specific branch. Taken together, our results provide a profound understanding about the underlying relationship between different lysine modifications and in situ crosstalk of different lysine modifications.