Comparative computational analysis of prion proteins reveals two fragments with unusual structural properties and a pattern of increase in hydrophobicity associated with disease-promoting mutations.

Prion diseases are a group of neurodegenerative disorders associated with conversion of a normal prion protein, PrPC, into a pathogenic conformation, PrPSc. The PrPSc is thought to promote the conversion of PrPC. The structure and stability of PrPC are well characterized, whereas little is known about the structure of PrPSc, what parts of PrPC undergo conformational transition, or how mutations facilitate this transition. We use a computational knowledge-based approach to analyze the intrinsic structural propensities of the C-terminal domain of PrP and gain insights into possible mechanisms of structural conversion. We compare the properties of PrP sequences to those of a PrP paralog, Doppel, and to the distributions of structural propensities observed in known protein structures from the Protein Data Bank. We show that the prion protein contains at least two sequence fragments with highly unusual intrinsic propensities, PrP(114-125) and helix B. No segments with unusual properties were found in Doppel protein, which is topologically identical to PrP but does not undergo structural rearrangements. Known disease-promoting PrP mutations form a statistically significant cluster in the region comprising helices B and C. Due to their unusual properties, PrP(114-125) and the C terminus of helix B may be considered as primary candidates for sites involved in conformational transition from PrPC to PrPSc. The results of our study also show that most PrP mutations associated with neurodegenerative disorders increase local hydrophobicity. We suggest that the observed increase in hydrophobicity may facilitate PrP-to-PrP or/and PrP-to-cofactor interactions, and thus promote structural conversion.