Diverse effects on the native β-sheet of the human prion protein due to disease-associated mutations.

Prion diseases are fatal neurodegenerative disorders that involve the conversion of the normal cellular form of the prion protein (PrP(C)) to a misfolded pathogenic form (PrP(Sc)). There are many genetic mutations of PrP associated with human prion diseases. Three of these point mutations are located at the first strand of the native β-sheet in human PrP: G131V, S132I, and A133V. To understand the underlying structural and dynamic effects of these disease-causing mutations on the human PrP, we performed molecular dynamics of wild-type and mutated human PrP. The results indicate that the mutations induced different effects but they were all related to misfolding of the native β-sheet: G131V caused the elongation of the native β-sheet, A133V disrupted the native β-sheet, and S132I converted the native β-sheet to an α-sheet. The observed changes were due to the reorientation of side chain-side chain interactions upon introducing the mutations. In addition, all mutations impaired a structurally conserved water site at the native β-sheet. Our work suggests various misfolding pathways for human PrP in response to mutation.