Regulation of proteolysis of intrinsically disordered proteins: physiological consequences

Abstract

Proteolysis represents a primary recycling system for amino acids. Moreover, by controlling the protein turnover, proteolysis plays an important role in key cellular processes such as control of cell cycle, programmed cell death (including senescence) and response to various stimuli. In eukaryotic cells, most proteins are degraded by autophagy and 26S proteasome machinery, composed in general of 20S proteolytic core and 19S regulatory particle. The protein susceptibility to proteolysis is determined by its structural features. Folded globular proteins in their native state are rarely degraded, however when misfolded, denatured or when an unstructured region is attached, the degradation is promoted. Proteins natively containing intrinsically disordered regions (IDRs) or completely lacking the stable secondary and tertiary structures are defined as intrinsically disordered proteins (IDPs). Due to their high intramolecular flexibility and plasticity, IDPs are involved in DNA metabolism, transcriptional activation, autophagy, and signalling cascades related to response to various stimuli. In sessile organisms such as plants, IDPs enable prompt acclimation to external factors, including light perception, adaptation to oxidative stress and water loss, and regulation of protective, antioxidative and secondary metabolism. Binding of specific ligands and partners to particular IDP triggers structural changes and affects the stability of IDP, its susceptibility to proteolysis and aggregation-propensity. Theabnormal aggregation of several IDPs and altered proteolysis pathways are closely connected with serious neurodegenerative disorders, such as Alzheimer’s and Parkinson's diseases. In this chapter, we discuss the current understanding of proteolytic processes of specific, well-characterised IDPs under different physiological states, emphasizing the influence of the microenvironment and ligands/partners on their conformation.