Structural and Dynamical Mechanisms of a Naturally Occurring Variant of the Human Prion Protein in Preventing Prion Conversion

TL;DR

This study uses molecular dynamics simulations to uncover how the V127 variant of human prion protein stabilizes its structure and prevents misfolding, offering insights into potential anti-prion strategies.

Contribution

It reveals the atomic-level mechanisms by which the V127 variant stabilizes prion protein and inhibits conversion, a novel insight into prion disease resistance.

Findings

G127V mutation increases S2-H2 loop rigidity

Enhances H2 C-terminal stability

Stabilizes overall PrP structure and prevents misfolding

Abstract

Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the beta-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2-H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2-H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.