Evidence for the role of PrP~c helix 1 in the hydrophilic seeding of prion aggregates

摘要

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 distri- bution) 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 forma- tion from two PrPc 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) bydrophobic aggregates.