Evidence for the role of PrPC helix 1 in the hydrophilic seeding of prion aggregates

AUTOR(ES)

Morrissey, M. P.

FONTE

The National Academy of Sciences

RESUMO

Prions are mammalian proteins (PrPs) with a unique pathogenic property: a nonendogenous isoform PrPSc can catalyze conversion of the endogenous PrPC isoform into additional PrPSc. In this work, we demonstrate that PrPC helix 1 has certain properties (hydrophilicity, charge distribution) that make it unique among all naturally occurring α-helices, and which are indicative of a highly specific model of prion infectivity. The β-nucleation model proposes that PrPSc is an aggregate with a hydrophilic core, consisting of a β-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 PrPC molecules is highly unfavorable, but the addition of chains to an existing aggregate is favorable. The β-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 β-nucleation, in contrast to the many proteins that readily form less favorable (often nonspecific) hydrophobic aggregates.

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