RT Journal Article SR Electronic(1) A1 Rigter, Alan A1 Bossers, AlexYR 2005 T1 Sheep scrapie susceptibility-linked polymorphisms do not modulate the initial binding of cellular to disease-associated prion protein prior to conversion JF Journal of General Virology, VO 86 IS 9 SP 2627 OP 2634 DO https://doi.org/10.1099/vir.0.80901-0 PB Microbiology Society, SN 1465-2099, AB Conversion of the host-encoded protease-sensitive cellular prion protein (PrPC) into the scrapie-associated protease-resistant isoform (PrPSc) 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 PrPC or PrPSc modulate the initial binding of PrPC to PrPSc, several naturally occurring allelic variants of sheep PrPC and PrPSc 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 in vivo differential scrapie susceptibility, it was found that the relative amounts of PrPC allelic variants bound by various allelic PrPSc 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 PrPC–PrPSc-binding efficiency, but seems to be an intrinsic property of PrPC itself. Consequently, a second step after PrPC–PrPSc-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 PrPC into PrPSc and supports the use of conversion-resistant polymorphic PrPC variants as a potential therapeutic approach to interfere with PrP conversion in transmissible spongiform encephalopathy development., UL https://www.microbiologyresearch.org/content/journal/jgv/10.1099/vir.0.80901-0