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Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates.

ABSTRACT: Prions are mammalian proteins (PrPs) with a unique pathogenic property: a nonendogenous isoform PrP(Sc) can catalyze conversion of the endogenous PrP(C) isoform into additional PrP(Sc). In this work, we demonstrate that PrP(C) helix 1 has certain properties (hydrophilicity, charge distribution) that make it unique among all naturally occurring alpha-helices, and which are indicative of a highly specific model of prion infectivity. The beta-nucleation model proposes that PrP(Sc) is an aggregate with a hydrophilic core, consisting of a beta-sheet-like arrangement of constituent helix 1 components. It is suggested by using structural arguments, and confirmed by using CHARMM energy calculations, that aggregate formation from two PrP(C) molecules is highly unfavorable, but the addition of chains to an existing aggregate is favorable. The beta-nucleation model is shown to be consistent with the prion species-barrier, as well as with infectivity data. Sequence analysis of all known protein structures indicates that PrP is uniquely suited to beta-nucleation, in contrast to the many proteins that readily form less favorable (often nonspecific) hydrophobic aggregates.

SUBMITTER: Morrissey MP

PROVIDER: S-EPMC18027 | biostudies-literature | 1999 Sep

REPOSITORIES: biostudies-literature

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Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates.

Morrissey M P MP Shakhnovich E I EI

Proceedings of the National Academy of Sciences of the United States of America 19990901 20

Prions are mammalian proteins (PrPs) with a unique pathogenic property: a nonendogenous isoform PrP(Sc) can catalyze conversion of the endogenous PrP(C) isoform into additional PrP(Sc). In this work, we demonstrate that PrP(C) helix 1 has certain properties (hydrophilicity, charge distribution) that make it unique among all naturally occurring alpha-helices, and which are indicative of a highly specific model of prion infectivity. The beta-nucleation model proposes that PrP(Sc) is an aggregate w ...[more]

PMID: 10500170

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Project description:The prion protein-encoding gene (prnp) strongly influences the susceptibility of small ruminants to transmissible spongiform encephalopathies (TSEs). Hence, selective breeding programs have been implemented to increase sheep resistance to scrapie. For goats, epidemiological and experimental studies have provided some association between certain polymorphisms of the cellular prion protein (PrP(C)) and resistance to TSEs. Among them, the Q/K polymorphism at PrP(C) codon 222 (Q/K222) yielded the most promising results. In this work, we investigated the individual effects of the K222-PrP(C) variant on the resistance/susceptibility of goats to TSEs. For that purpose, we generated two transgenic mouse lines, expressing either the Q222 (wild type) or K222 variant of goat PrP(C). Both mouse lines were challenged intracerebrally with a panel of TSE isolates. Transgenic mice expressing the wild-type (Q222) allele were fully susceptible to infection with all tested isolates, whereas transgenic mice expressing similar levels of the K222 allele were resistant to all goat scrapie and cattle BSE isolates but not to goat BSE isolates. Finally, heterozygous K/Q222 mice displayed a reduced susceptibility to the tested panel of scrapie isolates. These results demonstrate a highly protective effect of the K222 variant against a broad panel of different prion isolates and further reinforce the argument supporting the use of this variant in breeding programs to control TSEs in goat herds.The objective of this study was to determine the role of the K222 variant of the prion protein (PrP) in the susceptibility/resistance of goats to transmissible spongiform encephalopathies (TSEs). Results showed that transgenic mice expressing the goat K222-PrP polymorphic variant are resistant to scrapie and bovine spongiform encephalopathy (BSE) agents. This protective effect was also observed in heterozygous Q/K222 animals. Therefore, the single amino acid exchange from Q to K at codon 222 of the cellular prion protein provides resistance against TSEs. All the results presented here support the view that the K222 polymorphic variant is a good candidate for selective breeding programs to control and eradicate scrapie in goat herds.

Dataset Information

Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates.

Publications

Evidence for the role of PrP(C) helix 1 in the hydrophilic seeding of prion aggregates.

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