Influence of the pathogenic mutations T188K/R/A on the structural stability and misfolding of human prion protein: Insight from molecular dynamics simulations

Jingjing Guo, Lulu Ning, Hui Ren, Huanxiang Liu, Xiaojun Yao

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Background: Prion diseases are associated with a conformational switch for PrP from PrP C to PrP Sc. Many genetic mutations are linked with prion diseases, such as mutations T188K/R/A with fCJD. Scope of review: MD simulations for the WT PrP and its mutants were performed to explore the underlying dynamic effects of T188 mutations on human PrP. Although the globular domains are fairly conserved, the three mutations have diverse effects on the dynamics properties of PrP, including the shift of H1, the elongation of native β-sheet and the conversion of S2-H2 loop to a 3 10 helix. Major conclusions: Our present study indicates that the three mutants for PrP may undergo different pathogenic mechanisms and the realistic atomistic simulations can provide insights into the effects of disease-associated mutations on PrP dynamics and stability, which can enhance our understanding of how mutations induce the conversion from PrP C to PrP Sc. General significance Our present study helps to understand the effects of T188K/R/A mutations on human PrP: despite the three pathogenic mutations almost do not alter the native structure of PrP, but perturb its stability. This instability may further modulate the oligomerization pathways and determine the features of the PrP Sc assemblies.

Original languageEnglish
Pages (from-to)116-123
Number of pages8
JournalBiochimica et Biophysica Acta - General Subjects
Volume1820
Issue number2
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Keywords

  • Familial Creutzfeldt - Jakob disease
  • Familial prion disease
  • Molecular dynamics simulation
  • T188K/R/A mutant

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