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

ABSTRACT: 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 ?-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 ?-sheet: G131V caused the elongation of the native ?-sheet, A133V disrupted the native ?-sheet, and S132I converted the native ?-sheet to an ?-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 ?-sheet. Our work suggests various misfolding pathways for human PrP in response to mutation.

SUBMITTER: Chen W 

PROVIDER: S-EPMC2976833 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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

Chen Wei W   van der Kamp Marc W MW   Daggett Valerie V  

Biochemistry 20101022 45

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 p  ...[more]

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