From multifunctionality to polypathogenicity with intrinsic disorder
Year: 2023
Type: conference-paper
Abstract: Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structure \nunder physiological conditions in vitro. IDPs are characterized by an astonishing multilevel \nspatiotemporal heterogeneity, with their mosaic structure representing a complex \ncombination of foldons, inducible foldons, morphing inducible foldons, non-foldons, semifoldons, \nand unfoldons. \nIDPs are highly abundant in nature and have functional repertoire that is very \nbroad and complements functions of ordered proteins. Often, IDPs are involved in \nregulation, signaling and control pathways, commonly acting as hubs in protein-protein \ninteraction networks. Intrinsic disorder is an important constituent of the proteoform \nconcept, representing one of the important means of functional diversification of the \nproteinaceous products of a gene. Functions of IDPs may arise from specific disordered \nforms, from inter-conversion of disordered forms, or from order ←→ disorder transitions. \nThe choice between these conformations is determined by the peculiarities of the \nprotein environment, and many IDPs possess an exceptional ability to differently fold in a \ntemplate-dependent manner. As a result, many IDPs are capable of conducting multiple \nfunctions, with such multifunctionality being linked to their spatiotemporal heterogeneity. \nTherefore, a correlation between protein structure and function represents a “protein \nstructure–function continuum”, where a given protein exists as a dynamic conformational \nensemble containing multiple proteoforms characterized by diverse structural features \nand miscellaneous functions. \nIDPs are tightly controlled in the norm by various genetic and non-genetic mechanisms. \nAlteration in regulation of this disordered regulators are often detrimental to a cell, and \nmany IDPs are associated with a variety of human diseases, such as cancer, cardiovascular \ndisease, amyloidoses, neurodegenerative diseases, diabetes and others. Furthermore, \nmany IDPs are multipathogenic, being associated with the origination and development \nof a number of different diseases. Therefore, there is a though-provoking interconnection \nbetween intrinsic disorder, cell signaling, and human diseases, with polypathogenicity of \nthe involved proteins being linked to their structural plasticity and multifunctionality.
Author: N. Uversky, Vladimir
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7058473169