Solution Structure of a Prion Protein: Implications for Infectivity

Abstract

Prions cause neurodegenerative diseases in animals and humans. The scrapie prion protein (PrPSc) is the major – possibly only – component of the infectious prion and is generated from the cellular isoform (PrPC) by a conformational change. Limited proteolysis of PrPSc produces a polypeptide comprised primarily of residues 90 to 231, which retains infectivity. The three-dimensional structure of rPrP(90-231), a recombinant protein resembling PrPC with the Syrian hamster (SHa) sequence, was solved using multidimensional NMR. Low-resolution structures of rPrP(90-231), synthetic peptides up to 56 residues, a longer (29-231, full-length) protein with SHa sequence, and a shorter (121-231) protein with the mouse sequence have been previously reported. We report here further structure refinement of rPrP(90-231) and dynamic features of the protein. Consideration of these features in the context of published data suggests regions of conformational heterogeneity, structural elements involved in the PrPC  PrPSc transformation, and possible structural features related to a species barrier to transmission of prion diseases