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

Wei Chen, Marc W van der Kamp, Valerie Daggett

Research output: Contribution to journalArticle (Academic Journal)peer-review

34 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)9874-81
Number of pages8
JournalBiochemistry
Volume49
Issue number45
DOIs
Publication statusPublished - 16 Nov 2010

Keywords

  • Computer Simulation
  • Models, Molecular
  • Humans
  • Protein Folding
  • Prion Diseases
  • Amino Acid Sequence
  • PrPC Proteins
  • Prions
  • Mutation
  • Hydrogen Bonding
  • Protein Conformation

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