IEEE 7<sup>th</sup> BIBE Invited Tutorial Lecture: Intrinsically Disordered Proteins in Human Diseases

Abstract

Intrinsically disordered proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. They are highly abundant in nature, with ~25-30% of eukaryotic proteins being mostly disordered, and with >50% of eukaryotic proteins and > 70% of signaling proteins having long disordered regions. Functional repertoire of intrinsically disordered proteins is very broad and complements functions of ordered proteins. Often, intrinsically disordered proteins are involved in regulation, signaling and control pathways, where binding to multiple partners and high-speciflcity/low-afflnity interactions play a crucial role. We have found that out of the 711 Swiss-Prot functional keywords associated with at least 20 proteins, 262 were strongly positively correlated with long intrinsically disordered regions, and 302 were strongly negatively correlated. It is suggested that functions of intrinsically disordered proteins may arise from the specific disorder form, from inter-conversion of disordered forms, or from transitions between disordered and ordered conformations. The choice between these conformations is determined by the peculiarities of the protein environment, and many intrinsically disordered proteins possess an exceptional ability to fold in a template-dependent manner. Intrinsically disordered proteins are key players in protein-protein interaction networks being highly abundant among hubs. Furthermore, regions of mRNA which undergo alternative splicing code for disordered proteins much more often than they code for structured proteins. This association of alternative splicing and intrinsic disorder helps proteins to avoid folding difficulties and provides a novel mechanism for developing tissue-specific protein interaction networks. Numerous intrinsically disordered proteins are associated with such human diseases as cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, diabetes and others. Our bioinformatics analysis revealed that many human diseases are strongly correlated with proteins predicted to be disordered. Contrary to this, we did not find disease associated proteins to be strongly correlated with absence of disorder. Overall, there is an intriguing interconnection between intrinsic disorder, cell signaling and human diseases, which suggests that protein conformational diseases may result not only from protein misfolding, but also from misidentification and missignaling. Intrinsically disordered proteins, such as alpha-synuclein, tau protein, p53, BRCA1 and many other disease-associated hub proteins represent attractive targets for drugs modulating protein-protein interactions. Therefore, novel strategies for drug discovery are based on intrinsically disordered proteins.