Unexpected Tolerance of α-Cleavage of the Prion Protein to Sequence VariationsReport as inadecuate

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The cellular form of the prion protein, PrPC, undergoes extensive proteolysis at the α site 109K↓H110. Expression of non-cleavable PrPC mutants in transgenic mice correlates with neurotoxicity, suggesting that α-cleavage is important for PrPC physiology. To gain insights into the mechanisms of α-cleavage, we generated a library of PrPC mutants with mutations in the region neighbouring the α-cleavage site. The prevalence of C1, the carboxy adduct of α-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 α-cleavage site, and by substitutions of the residues in the palindrome that flanks this site. Instead, α-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 α-cleavage is executed by an α-PrPase whose activity, despite surprisingly limited sequence specificity, is dependent on the size of the central region of PrPC.

Author: José B. Oliveira-Martins, Sei-ichi Yusa, Anna Maria Calella, Claire Bridel, Frank Baumann, Paolo Dametto, Adriano Aguzzi

Source: http://plos.srce.hr/


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