The identical protein precursor encoded by the identical gene is capable of forming mature proteins with opposing phenotypes or distinct functions via different posttranslational modifications (PTMs), which alter its localization, interaction, and conformation. This substantially enhances the complexity and functionality of the proteome. Among these PTMs, glycosylation, being the most intricate and vital type, mediates the functional reversal of proteins from tumor suppression to tumor promotion through competitive modification and serves as the core regulatory factor of PTM-driven role reversal (PDRR). This functional reversal not only redefines disease subtypes but also creates an opportunity for precise treatment, presenting significant theoretical and clinical value. This article will focus on delineating the three levels of PDRR formation: the roles and specific regulatory instances of Topological Fate Switch (TFS), Biased Signaling Switch (BSS), and Phase/Oligomerization Switch (POS). Simultaneously, given the immense challenges in researching PTMs, it is essential to combine them with certain cutting-edge technologies to elevate the influence of PTMs on protein function from the theoretical level to technological highlights and integrate omics with spatial and single-cell analysis, live-cell imaging, and chemical biology. The relationship between PTMs and various physiological or pathological conditions is investigated at the level of individual cells or individual protein molecules. Owing to the crucial role of PTM enzymes in diseases, they have emerged as highly attractive drug targets, signifying the clinical translational value of the theory of PTMs and the three switches. That is, to link writer enzymes, eraser enzymes, and reader enzymes with measurable PTM profiles as drug targets and biomarkers, offering novel design and research concepts and directions for the development of new drugs.
Lu et al. (Wed,) studied this question.