An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity
| Autor: | Isaac H. Solomon, Emiliano Biasini, David A. Harris, Natasha Khatri, Tania Massignan, James E. Huettner |
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| Rok vydání: | 2011 |
| Předmět: |
Cytoplasm
Prions animal diseases Mutant Detergents Biology medicine.disease_cause Biochemistry Cell Line Prion Diseases Cell membrane Mice medicine Animals Humans Molecular Biology Cellular localization chemistry.chemical_classification Ions Mutation Point mutation Cell Membrane Neurodegenerative Diseases Molecular Bases of Disease Cell Biology Amino acid nervous system diseases Protein Structure Tertiary Electrophysiology medicine.anatomical_structure chemistry Cell culture Cell culture assays Gene Deletion |
| Zdroj: | The Journal of biological chemistry. 286(16) |
| ISSN: | 1083-351X |
| Popis: | There is evidence that alterations in the normal physiological activity of PrP(C) contribute to prion-induced neurotoxicity. This mechanism has been difficult to investigate, however, because the normal function of PrP(C) has remained obscure, and there are no assays available to measure it. We recently reported that cells expressing PrP deleted for residues 105-125 exhibit spontaneous ionic currents and hypersensitivity to certain classes of cationic drugs. Here, we utilize cell culture assays based on these two phenomena to test how changes in PrP sequence and/or cellular localization affect the functional activity of the protein. We report that the toxic activity of Δ105-125 PrP requires localization to the plasma membrane and depends on the presence of a polybasic amino acid segment at the N terminus of PrP. Several different deletions spanning the central region as well as three disease-associated point mutations also confer toxic activity on PrP. The sequence domains identified in our study are also critical for PrP(Sc) formation, suggesting that common structural features may govern both the functional activity of PrP(C) and its conversion to PrP(Sc). |
| Databáze: | OpenAIRE |
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