Different misfolding mechanisms converge on common conformational changes: human prion protein pathogenic mutants Y218N and E196K.

ABSTRACT: Prion diseases are caused by misfolding and aggregation of the prion protein (PrP). Pathogenic mutations such as Y218N and E196K are known to cause Gerstmann-Sträussler-Scheinker syndrome and Creutzfeldt-Jakob disease, respectively. Here we describe molecular dynamics simulations of these mutant proteins to better characterize the detailed conformational effects of these sequence substitutions. Our results indicate that the mutations disrupt the wild-type native PrP(C) structure and cause misfolding. Y218N reduced hydrophobic packing around the X-loop (residues 165-171), and E196K abolished an important wild-type salt bridge. While differences in the mutation site led PrP mutants to misfold along different pathways, we observed multiple traits of misfolding that were common to both mutants

SUBMITTER: Cheng CJ 

PROVIDER: S-EPMC7030917 | biostudies-literature | 2014 Jan-Feb

REPOSITORIES: biostudies-literature