Polymorphisms Modulate Sheep Prion Protein Susceptibility to Misfolding by Altering the Residue Network of Interactions

Abstract

The autocatalytic misfolding of the cellular form of the prion protein, PrPC, to the infectious form, PrPSc, is critical to the development of prion diseases. Though the mechanism for this misfolding is not well understood, previous research recognizes the role of genetic mutations in varying susceptibilities to prion diseases in sheep. Using structural bioinformatics techniques, our study examines the residue interactions in three different sheep PrPC structures. These structures contain different point mutations and have different levels of susceptibility to scrapie prion disease. We will discuss our results in relation to the role of mutations on networks of interaction, and propose a mechanism for the primary misfolding of the a-helical rich PrPC into the b-sheet rich PrPSc. This work was made possible partly by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), and its contents are the sole responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.