Genetic influence on the structural variations of the abnormal prion protein

Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10168-72. doi: 10.1073/pnas.97.18.10168.


Prion diseases are characterized by the presence of the abnormal prion protein PrP(Sc), which is believed to be generated by the conversion of the alpha-helical structure that predominates in the normal PrP isoform into a beta-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrP(Sc), type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrP(Sc) in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrP(Sc), respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrP(Sc): one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Brain Chemistry*
  • Codon
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Endopeptidase K
  • Genetic Variation*
  • Humans
  • Kuru / genetics*
  • Peptide Fragments / chemistry
  • PrPSc Proteins / chemistry
  • PrPSc Proteins / genetics*
  • Protein Conformation


  • Codon
  • Peptide Fragments
  • PrPSc Proteins
  • Endopeptidase K