en
Scientific article
Open access
English

Unexpected tolerance of alpha-cleavage of the prion protein to sequence variations

Published inPloS one, vol. 5, no. 2, e9107
Publication date2010-02-08
First online date2010-02-08
Abstract

The cellular form of the prion protein, PrP(C), undergoes extensive proteolysis at the alpha site (109K [see text]H110). Expression of non-cleavable PrP(C) mutants in transgenic mice correlates with neurotoxicity, suggesting that alpha-cleavage is important for PrP(C) physiology. To gain insights into the mechanisms of alpha-cleavage, we generated a library of PrP(C) mutants with mutations in the region neighbouring the alpha-cleavage site. The prevalence of C1, the carboxy adduct of alpha-cleavage, was determined for each mutant. In cell lines of disparate origin, C1 prevalence was unaffected by variations in charge and hydrophobicity of the region neighbouring the alpha-cleavage site, and by substitutions of the residues in the palindrome that flanks this site. Instead, alpha-cleavage was size-dependently impaired by deletions within the domain 106-119. Almost no cleavage was observed upon full deletion of this domain. These results suggest that alpha-cleavage is executed by an alpha-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrP(C).

eng
Keywords
  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line
  • Glycosylation
  • HeLa Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • NIH 3T3 Cells
  • Peptide Hydrolases / metabolism
  • PrPC Proteins / chemistry
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism
  • PrPSc Proteins / genetics
  • PrPSc Proteins / metabolism
  • Prion Proteins
  • Prions / chemistry
  • Prions / genetics
  • Prions / metabolism
  • Sequence Homology, Amino Acid
Affiliation Not a UNIGE publication
Citation (ISO format)
OLIVEIRA-MARTINS, José B et al. Unexpected tolerance of alpha-cleavage of the prion protein to sequence variations. In: PloS one, 2010, vol. 5, n° 2, p. e9107. doi: 10.1371/journal.pone.0009107
Main files (1)
Article (Published version)
Secondary files (1)
Identifiers
ISSN of the journal1932-6203
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