Exploring the Propensities of Helices in PrP C to Form β Sheet Using NMR Structures and Sequence Alignments

Abstract

Neurodegenerative diseases induced by transmissible spongiform encephalopathies are associated with prions. The most spectacular event in the formation of the infectious scrapie form, referred to as PrP Sc, is the conformational change from the predominantly α-helical conformation of PrP C to the PrP Sc state that is rich in β-sheet content. Using sequence alignments and structural analysis of the available nuclear magnetic resonance structures of PrP C, we explore the propensities of helices in PrP C to be in a β-strand conformation. Comparison of a number of structural characteristics (such as solvent accessible area, distribution of (Φ, Ψ) angles, mismatches in hydrogen bonds, nature of residues in local and nonlocal contacts, distribution of regular densities of amino acids, clustering of hydrophobic and hydrophilic residues in helices) between PrP C structures and a databank of “normal” proteins shows that the most unusual features are found in helix 2 (H2) (residues 172–194) followed by helix 1 (H1) (residues 144–153). In particular, the C-terminal residues in H2 are frustrated in their helical state. The databank of normal proteins consists of 58 helical proteins, 36 α+ β proteins, and 31 β-sheet proteins. Our conclusions are also substantiated by gapless threading calculations that show that the normalized Z-scores of prion proteins are similar to those of other α+ β proteins with low helical content. Application of the recently introduced notion of discordance, namely, incompatibility of the predicted and observed secondary structures, also points to the frustration of H2 not only in the wild type but also in mutants of human PrP C. This suggests that the instability of PrP C proteins may play a role in their being susceptible to the profound conformational change. Our analysis shows that, in addition to the previously proposed role for the segment (90–120) and possibly H1, the C-terminus of H2 and possibly N-terminus may play a role in the α→ β transition. An implication of our results is that the ease of polymerization depends on the unfolding rate of the monomer. Sequence alignments show that helices in avian prion proteins (chicken, duck, crane) are better accommodated in a helical state, which might explain the absence of PrP Sc formation over finite time scales in these species. From this analysis, we predict that correlated mutations that reduce the frustration in the second half of helix 2 in mammalian prion proteins could inhibit the formation of PrP Sc.