Emerging Role of Mass Spectrometry-Based Structural Proteomics in Elucidating Intrinsic Disorder in Proteins

Inherent disorder is an integral part of all proteomes, represented as fully or partially unfolded proteins. The lack of order in intrinsically disordered proteins (IDPs) results in an incredibly flexible, floppy, and heterogeneous ensemble, contrary to the well-structured and unique organization of folded proteins. Despite such unusual demeanor, IDPs are crucial for numerous cellular processes and are increasingly being associated with disease-causing pathologies. These warrant more intensive investigation of this atypical class of protein. Traditional biophysical tools, however, fall short of analyzing IDPs, thus making their structure-function characterization challenging. Mass spectrometry (MS) in recent years has evolved as a valuable tool for elucidating the unusual conformational facets of IDPs. In this review, the features of advanced MS techniques such as Hydrogen-deuterium exchange (HDX)-MS, native MS, limited proteolysis (LiP)-MS, chemical cross-linking (XL)-MS, and Fast photochemical oxidation of proteins (FPOP)-MS are briefly discussed. Recent MS studies on IDPs and the unique advantages/shortfalls associated with the above methods while evaluating structural proteomics of IDPs, are illustrated. Eventually the future scope of the MS methods in further decoding the unexplored landscapes of IDPs is presented.