Structural facets of disease‐linked human prion protein mutants: A molecular dynamic study

Abstract

Prion propagation in transmissible spongiform encephalopathies involves the conversion of the cellular prion protein, PrPC, into the pathogenic conformer PrPSc. Human familial forms of the disease are linked to specific mutations in the PrP gene, PRNP, and include Gerstmann-Strussler-Scheinker syndrome (GSS), familial Creutzfeldt-Jakob disease (fCJD), and fatal familial insomnia. To gain insights into the molecular basis of these disorders, we performed 200 ns of classical molecular dynamic simulations in aqueous solution on wild type (WT) human PrP (HuPrP), and on three HuPrP variants located in the globular HuPrP domain: two pathological mutations, HuPrP(Q212P) and HuPrP(E200K), linked to GSS and to fCJD respectively, and one protective polymorphism, HuPrP(E219K) (total time-scale simulated 800 ns). A comparison between the predicted structural determinants of WT HuPrP and HuPrP(E200K) with their NMR structures established the accuracy of the methods used. Strikingly, the analyzed disease-linked variants produced their major effect on the α2-α3 region and the β2-α2 loop, regardless of the mutation position. The conformational change of the latter might affect the interactions with cellular partners in the fibrillation process. The protocol proposed here represents a powerful approach for reproducing the structural effects of genetic mutations located in the globular domain of HuPrP, such as the GSS-related HuPrP(Q212P) and the protective polymorphism HuPrP(E219K).

Structural plasticity of the cellular prion protein and implications in health and disease

“…This result is also obtained for mPrP C , where the observed line broadening can be rationalized by conformational exchange between two precisely defined, locally different structures (28). There are, by now, numerous model simulations focused on the β2-α2 loop in PrP C (29)(30)(31)(32)(33), and continuation of work along these lines will greatly benefit from a more comprehensive platform of experimental data.…”

“…(ii) The residue position 168 is polymorphic in sheep PrP, and the residue type in this position affects susceptibility of sheep to scrapie (51)(52)(53)(54). (iii) For TSE-sensitive mutants of PrP C , molecular dynamics simulations indicate a trend for solvent exposure of Y169 (29)(30)(31)(32)(33), leading to increased hydrophobicity of the loop surface, which has been related to increased cytotoxicity of prion proteins (55,56). The conformations with exposed Y169 that are observed in the molecular dynamics simulations are similar to the type I β-turn loop conformation (Fig.…”

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…The latter type of pathogenic mutation has been found in at least 28 different locations, and effects on protein stability, misfolding as well as cellular processing and function are reported [123]. MD simulations can be used to study the effect of these mutations on protein conformation and stability, particularly for the 24 mutations that are found in the C-terminal folded domain of human PrP [124][125][126]. Structural biology can also offer insights into the structural effect of pathogenic mutations [75,127] (see also chapter Y by Surewicz et al).…”

Common Structural Traits across Pathogenic Mutants of the Human Prion Protein and Their Implications for Familial Prion Diseases

“…Molecular dynamics (MD) simulations have provided insights into the structural determinants and the plasticity of several other variants associated with DLMs 41-53,63-68 having a large incidence in the disease, 15 as well as the protective polymorphism HuPrP(E219K-129M) [HuPrP(PP) hereinafter] ‡. 43 All of these studies have shown that the secondary and tertiary elements are similar across all these variants.…”