Unexpected Tolerance of [alpha]-Cleavage of the Prion Protein to Sequence Variations

The cellular form of the prion protein, PrP.sup.C, undergoes extensive proteolysis at the [alpha] site (109K[down-pointing arrow]H110). Expression of non-cleavable PrP.sup.C mutants in transgenic mice correlates with neurotoxicity, suggesting that [alpha]-cleavage is important for PrP.sup.C physiolo...

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Bibliographic Details
Published in:PloS one 2010-02, Vol.5 (2), p.e9107
Main Authors: Oliveira-Martins, José B, Yusa, Sei-ichi, Calella, Anna Maria, Bridel, Claire, Baumann, Frank, Dametto, Paolo, Aguzzi, Adriano
Format: Article
Language:English
Subjects:
Amino acids
Physiological aspects
Prions (Proteins)
Proteolysis
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Summary:The cellular form of the prion protein, PrP.sup.C, undergoes extensive proteolysis at the [alpha] site (109K[down-pointing arrow]H110). Expression of non-cleavable PrP.sup.C mutants in transgenic mice correlates with neurotoxicity, suggesting that [alpha]-cleavage is important for PrP.sup.C physiology. To gain insights into the mechanisms of [alpha]-cleavage, we generated a library of PrP.sup.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.sup.C.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0009107