1887

Abstract

Conversion of the host-encoded protease-sensitive cellular prion protein (PrP) into the scrapie-associated protease-resistant isoform (PrP) of prion protein (PrP) is the central event in transmissible spongiform encephalopathies or prion diseases. Differences in transmissibility and susceptibility are largely determined by polymorphisms in PrP, but the exact molecular mechanism behind PrP conversion and the modulation by disease-associated polymorphisms is still unclear. To assess whether the polymorphisms in either PrP or PrP modulate the initial binding of PrP to PrP, several naturally occurring allelic variants of sheep PrP and PrP that are associated with differential scrapie susceptibility and transmissibility [the phylogenetic wild-type (ARQ), the codon 136Val variant (VRQ) and the codon 171Arg variant (ARR)] were used. Under cell-free PrP conversion conditions known to reproduce the observed differential scrapie susceptibility, it was found that the relative amounts of PrP allelic variants bound by various allelic PrP variants are PrP-specific and have comparable binding efficiencies. Therefore, the differential rate-limiting step in conversion of sheep PrP variants is not determined by the initial PrP–PrP-binding efficiency, but seems to be an intrinsic property of PrP itself. Consequently, a second step after PrP–PrP-binding should determine the observed differences in PrP conversion efficiencies. Further study of this second step may provide a future tool to determine the mechanism underlying refolding of PrP into PrP and supports the use of conversion-resistant polymorphic PrP variants as a potential therapeutic approach to interfere with PrP conversion in transmissible spongiform encephalopathy development.

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2005-09-01
2019-11-19
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