Copper(II)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation |
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Authors: | Qin K Yang D S Yang Y Chishti M A Meng L J Kretzschmar H A Yip C M Fraser P E Westaway D |
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Institution: | Centre for Research in Neurodegenerative Diseases, Department of Medical Biophysics, Mass Spectrometry Laboratory, Modern Medicine Research Centre, Toronto, Ontario M 5S 3HS, Canada. |
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Abstract: | While PrP(C) rearranges in the area of codons 104-113 to form PrP(Sc) during prion infections, the events that initiate sporadic Creutzfeldt-Jakob disease are undefined. As Cu(II) is a putative ligand for PrP(C) and has been implicated in the pathogenesis of Creutzfeldt-Jakob disease and other neurodegenerative diseases, we investigated the structural effects of binding. Incubation of brain microsomes with Cu(II) generated approximately 30-kDa proteinase K-resistant PrP. Cu(II) had little effect on fresh recombinant PrP23-231, but aged protein characterized by conversion of Asn-107 to Asp decreased alpha-helical content by approximately 30%, increased beta-sheet content 100%, formed aggregates, and acquired proteinase K resistance in the presence of Cu(II). These transitions took place without need for acid pH, organic solvents, denaturants, or reducing agents. Since conversion of Asn to Asp proceeds by a spontaneous pathway involving deamidation, our data suggest that covalent variants of PrP(C) arising in this manner may, in concert with Cu(II), generate PrP(Sc)-like species capable of initiating sporadic prion disease. |
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