DbPTM in 2019: exploring disease association and cross-talk of post-translational modifications.

Hsien-Da Huang,Tsai-Hsuan Lin,Chen-Tse Ma,Wen-Chi Chang,Chao-Chun Lee,Kai-Yao Huang,Hui-Ju Kao,Tzong-Yi Lee

doi:10.1093/nar/gky1074

Abstract

The dbPTM (http://dbPTM.mbc.nctu.edu.tw/) has been maintained for over 10 years with the aim to provide functional and structural analyses for post-translational modifications (PTMs). In this update, dbPTM not only integrates more experimentally validated PTMs from available databases and through manual curation of literature but also provides PTM-disease associations based on non-synonymous single nucleotide polymorphisms (nsSNPs). The high-throughput deep sequencing technology has led to a surge in the data generated through analysis of association between SNPs and diseases, both in terms of growth amount and scope. This update thus integrated disease-associated nsSNPs from dbSNP based on genome-wide association studies. The PTM substrate sites located at a specified distance in terms of the amino acids encoded from nsSNPs were deemed to have an association with the involved diseases. In recent years, increasing evidence for crosstalk between PTMs has been reported. Although mass spectrometry-based proteomics has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that the crosstalk of combinatorial PTMs may act in concert with the regulation of protein function and activity is neglected. Because of the relatively limited information about concurrent frequency and functional relevance of PTM crosstalk, in this update, the PTM sites neighboring other PTM sites in a specified window length were subjected to motif discovery and functional enrichment analysis. This update highlights the current challenges in PTM crosstalk investigation and breaks the bottleneck of how proteomics may contribute to understanding PTM codes, revealing the next level of data complexity and proteomic limitation in prospective PTM research.

Highlights

Protein post-translational modifications (PTMs) are one of the most important mechanisms of eukaryotic and prokaryotic cells, which involve the attachment of chemical groups to amino acid side chains of proteins [1,2]
Protein phosphorylation is the most ubiquitous PTM that induces signal transduction and cell apoptosis [5]; protein acetylation and methylation are involved in chromatin reprogramming and transcriptional regulation [6,7]; lysine glutarylation plays a crucial role in metabolic pathways and mitochondrial functions [8]; lysine ubiquitination mediates protein degradation [9]; protein glycosylation is in charge of controlling the cell-extracellular matrix interactions [10,11]
With the dramatic increase of online PTM resources, dbPTM has been dedicated to the development of a resource portal to integrate as many as possible online resources for PTM analyses

Summary

Introduction

Protein post-translational modifications (PTMs) are one of the most important mechanisms of eukaryotic and prokaryotic cells, which involve the attachment of chemical groups to amino acid side chains of proteins [1,2]. The highlighted improvements and advances in the dbPTM 2019 update are displayed in Supplementary Figure S1, including (i) update of the experimental PTM dataset from published databases and literature, (ii) update of the benchmark datasets for PTM analyses, (iii) update of the existing PTM-related databases and tools, (iv) investigation of PTM-disease associations based on single amino acid polymorphisms (SAPs), (v) investigation of PTM crosstalk between two different modification types and (vi) improvement of the user interface.

Results

Conclusion