Simulations of membrane-bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Chin Jung Cheng, University of Washington, Seattle
  • ,
  • Heidi Koldso, University of Washington, Seattle
  • ,
  • Marc W. Van der Kamp, University of Washington, Seattle
  • ,
  • Birgit Schiott
  • Valerie Daggett, University of Washington, Seattle

Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrPC) to its infectious scrapie form (PrPSc). Post-translational modifications in PrP invivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of post-translational modifications in PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrPC bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein-only PrPC, no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrPSc oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrPSc-induced misfolding of PrPC.

Original languageEnglish
JournalJournal of Neurochemistry
Volume142
Issue1
Pages (from-to)171-182
Number of pages12
ISSN0022-3042
DOIs
Publication statusPublished - Jul 2017

    Research areas

  • membrane simulation, molecular dynamics, prion protein misfolding, MOLECULAR-DYNAMICS SIMULATIONS, BETA-SHEET, CELL-SURFACE, FULL-LENGTH, PATHOGENIC MUTATIONS, ANCHORED PRION, NUCLEIC-ACIDS, STERIC ZIPPER, EARLY STEPS, CONVERSION

See relations at Aarhus University Citationformats

ID: 115156745