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pubmed:abstractText |
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.
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