After four decades of prion protein research, the pressing questions in the literature remain similar to the common existential dilemmas. Who am I? Some structural characteristics of the cellular prion protein (PrPC) and scrapie PrP (PrPSc) remain unknown: there are no high-resolution atomic structures for either full-length endogenous human PrPC or isolated infectious PrPSc particles. Why am I here? It is not known why PrPC and PrPSc are found in specific cellular compartments such as the nucleus; while the physiological functions of PrPC are still being uncovered, the misfolding site remains obscure. Where am I going? The subcellular distribution of PrPC and PrPSc is wide (reported in 10 different locations in the cell). This complexity is further exacerbated by the eight different PrP fragments yielded from conserved proteolytic cleavages and by reversible post-translational modifications, such as glycosylation, phosphorylation, and ubiquitination. Moreover, about 55 pathological mutations and 16 polymorphisms on the PrP gene (PRNP) have been described. Prion diseases also share unique, challenging features: strain phenomenon (associated with the heterogeneity of PrPSc conformations) and the possible transmissibility between species, factors which contribute to PrP undruggability. However, two recent concepts in biochemistry-intrinsically disordered proteins and phase transitions-may shed light on the molecular basis of PrP's role in physiology and disease.
Keywords: Biomolecular condensate; Intrinsic disorder; Liquid droplets; Liquid-liquid phase separation; Misfolding diseases; Nucleic acids; Phase transitions; Prion diseases; Prion protein; Protein aggregation.
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