Prion dimer is heterogenous and is modulated by multiple negative and positive motifs

Biochem Biophys Res Commun. 2019 Feb 5;509(2):570-576. doi: 10.1016/j.bbrc.2018.12.113. Epub 2018 Dec 29.


The conversion of the normal prion protein (PrP) into a scrapie prion (PrPSc) is incompletely understood. Theoretically, the smallest PrP aggregate is a dimer. Human PrP contains two cysteines at positions 179 (C179) and 214 (C214) enabling disulfide bonding. Here, we report that our recombinant human PrP (r-hPrP) preparations contain 0.2-0.8% dimer, which is linked by either one or two disulfide bonds, connected by C179-C179, C214-C214, or C179-C214. Furthermore, dimerization is regulated by multiple motifs. While residues 36-42 inhibit, residues 90-125, and 195-212 promote dimerization. Mutating individual residue between 36 and 42 enhances dimerization whereas mutating the positively charged residues within 95-115, or the negatively charged residues within 195-212 prevent dimerization. Although deletion of the entire octapeptide-repeat (5OR) region prevents dimerization, mutating the histidines within the 5OR enhances dimerization. In addition, we found that two out of three brain lysates from patients with inherited prion disease had more PrP dimers than controls. Thus, PrP dimerization may contribute to prion diseases.

Keywords: Disulfide bond; Fatal familial insomnia; PrP aggregation; PrP dimer; Prion protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / analysis
  • Amino Acids / genetics
  • Brain / metabolism
  • Brain / pathology*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Insomnia, Fatal Familial / genetics
  • Insomnia, Fatal Familial / pathology*
  • Point Mutation
  • Prion Proteins / chemistry*
  • Prion Proteins / genetics
  • Protein Domains
  • Protein Multimerization*


  • Amino Acids
  • Prion Proteins