Small Changes Huge Impact: The Role of Protein Posttranslational Modifications in Cellular Homeostasis and Disease

Posttranslational modifications (PTMs) modulate protein function in most eukaryotes and have a ubiquitous role in diverse range of cellular functions. Identification, characterization, and mapping of these modifications to specific amino acid residues on proteins are critical towards understanding their functional significance in a biological context. The interpretation of proteome data obtained from the high-throughput methods cannot be deciphered unambiguously without a priori knowledge of protein modifications. An in-depth understanding of protein PTMs is important not only for gaining a perception of a wide array of cellular functions but also towards developing drug therapies for many life-threatening diseases like cancer and neurodegenerative disorders. Many of the protein modifications like ubiquitination play a decisive role in various drug response(s) and eventually in disease prognosis. Thus, many commonly observed PTMs are routinely tracked as disease markers while many others are used as molecular targets for developing target-specific therapies. In this paper, we summarize some of the major, well-studied protein alterations and highlight their importance in various chronic diseases and normal development. In addition, other promising minor modifications such as SUMOylation, observed to impact cellular dynamics as well as disease pathology, are mentioned briefly. 1. Introduction With current advances in the fields of systems biology and proteomics, the interest in deciphering protein modifications and their impact on the cellular microenvironment and disease pathophysiology is greatly enhanced. Proteins are large macromolecules comprised of a specific sequence of amino acids. Although protein folding and refolding play a critical role in protein function, the modification of amino acids and their side chains contributes significantly to the structural and functional diversity of the proteins. These modifications impart complexity to the eukaryotic proteomes that is several orders of magnitude greater than the coding capacity of the genome. The common modifications include phosphorylation, acetylation, glycosylation, ubiquitination, acetylation, and hydroxylation. Posttranslational modifications (PTMs) of proteins influence the enzyme activity, protein turnover and localization, protein-protein interactions, modulation for various signaling cascades, DNA repair, and cell division. Given the pivotal role of PTMs in the regulation of cellular environment, there is a constant effort to develop novel, highly sensitive, and sophisticated PTM