期刊
PLOS ONE
卷 5, 期 2, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0009107
关键词
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资金
- Swiss National Foundation
- European Union
- National Competence Center on Neural Plasticity and Repair
- Stammbach foundation
- Novartis Foundation
- European Research Council
- Portuguese Foundation for Science and Technology
- Instituto Gulbenkian de Ciencia
The cellular form of the prion protein, PrPC, undergoes extensive proteolysis at the alpha site (109K down arrow H110). Expression of non-cleavable PrPC mutants in transgenic mice correlates with neurotoxicity, suggesting that alpha-cleavage is important for PrPC physiology. To gain insights into the mechanisms of alpha-cleavage, we generated a library of PrPC 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 PrPC.
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