The language of posttranslational modifications and deciphering it from proteomics data

Posttranslational modifications (PTMs) of proteins are covalent functional groups at specific amino acid residues that extend the regulatory function of the proteins. The modifications control enzyme activity, subcellular localization, signaling, structural conformation, protein–protein interactions (PPIs), multiprotein complex formation, and assembly. Their dysregulation is known to cause perturbed signaling and leads to diseases like cancer, diabetes, cardiovascular, neurodegenerative disorders, infectious, and other metabolic diseases. Systems level understanding of these processes in health and disease is a key to find useful drug targets, biomarkers, and therapeutic strategies. Shotgun proteomics using mass spectrometry (MS) is a high-throughput method that allows identification and quantification of proteins and their modifications in diverse biological systems. Most PTMs are substoichiometric and effective at low abundance in nature due to their primarily signaling roles. Thus, a protein may appear to be quantitatively similar between different biological conditions, even though different mod-forms of the protein may be differentially expressed. It is imperative that any systems wide study using proteomics should profile the changes in modification status of a cell. However, this measurement depends on a robust experimental design coupled with strong computational analysis. Here, we highlight the functional roles of several key modifications in cancer and several other diseases. We describe the optimal methods for PTMs discovery from proteomics data, keeping in mind the various challenges involved in the process, with an emphasis on the analysis tools. We also discuss tools and resources for biological and functional interpretation of modifications data. We conclude with the promises and challenges of integrating modifications in mainstream biology for fundamental and translational advances.