Probing the role of RNA in prion protein and prion fibril recognition.

Abstract

The conversion of the cellular form of the prion protein PrPC to the misfolded and aggregated form PrPSc is the key pathological event in prion diseases, yet the mechanism of the conformational change remains unknown. Evidence suggests that prion protein misfolding initiates on the cell surface, where the prion protein is GPI anchored to the outer leaflet of the plasma membrane. Compelling results document that extracellularly located nucleic acids scaffold prion protein aggregation; however, whether nucleic acids interact directly with the monomer prion protein, a misfolded intermediate, or PrPSc fibrils remains unknown. Recent studies indicate upon RNA binding, a pincer-like structure is formed between the N-terminus and a-helix 1 of the prion protein that traps the RNA and induces misfolding of the helix. However, it is unknown how the initial misfolding of a-helix 1 affects the other helices. To fill this gap, we aim to examine the changes in protein and fibril connectivity as well as identify key residues involved in RNA mediated aggregation of the prion protein. We used structural bioinformatics techniques to model and examine the connectivity of the prion protein and prion fibrils when bound to RNA. Our results suggest that the binding of RNA to a-helix 1 modulates the long-distance coupling to other helices. We will also probe the modulatory effects of RNA on the interactions between prion protein and fibrils. We will use these calculations to infer the role of RNA on prion protein misfolding and protein-fibril recognition.