Intrinsic disorder and phase transitions: Pieces in the puzzling role of the prion protein in health and disease.

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 (PrP) and scrapie PrP (PrP) remain unknown: there are no high-resolution atomic structures for either full-length endogenous human PrP or isolated infectious PrP particles. Why am I here? It is not known why PrP and PrP are found in specific cellular compartments such as the nucleus; while the physiological functions of PrP are still being uncovered, the misfolding site remains obscure. Where am I going? The subcellular distribution of PrP and PrP 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 PrP 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.