Vladimir N. Uversky1
1Department of Molecular Medicine and USF Health Byrd Alzheimer’s Center and Research Institute, University of South Florida, Tampa, Florida 33612, USA
vuversky [at] usf.edu
Abstract
Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structure under physiological conditions in vitro. IDPs are characterized by an astonishing multi-level spatiotemporal heterogeneity, with their mosaic structure representing a complex combination of foldons, inducible foldons, morphing inducible foldons, non-foldons, semi-foldons, and unfoldons.
IDPs are highly abundant in nature and have functional repertoire that is very broad and complements functions of ordered proteins. Often, IDPs are involved in regulation, signaling and control pathways, commonly acting as hubs in protein-protein interaction networks. Intrinsic disorder is an important constituent of the proteoform concept, representing one of the important means of functional diversification of the proteinaceous products of a gene. Functions of IDPs may arise from specific disordered forms, from inter-conversion of disordered forms, or from order ↔ disorder transitions. The choice between these conformations is determined by the peculiarities of the protein environment, and many IDPs possess an exceptional ability to differently fold in a template-dependent manner. As a result, many IDPs are capable of conducting multiple functions, with such multifunctionality being linked to their spatiotemporal heterogeneity. Therefore, a correlation between protein structure and function represents a “protein structure–function continuum”, where a given protein exists as a dynamic conformational ensemble containing multiple proteoforms characterized by diverse structural features and miscellaneous functions.
IDPs are tightly controlled in the norm by various genetic and non-genetic mechanisms. Alteration in regulation of this disordered regulators are often detrimental to a cell, and many IDPs are associated with a variety of human diseases, such as cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, diabetes and others. Furthermore, many IDPs are multipathogenic, being associated with the origination and development of a number of different diseases. Therefore, there is a though-provoking interconnection between intrinsic disorder, cell signaling, and human diseases, with polypathogenicity of the involved proteins being linked to their structural plasticity and multifunctionality.
Keywords: intrinsically disordered protein, multifunctionality, polypathogenicity, structure-function continuum
