The Prion Switch Unravelled

Abstract

The post‐translational conversion of the cellular prion protein (PrPC) into the misfolded, pathogenic scrapie isoform (PrPSc) plays a key role in prion diseases. PrPC interacts with metal ions, in particular copper, through the octarepeat and non‐octarepeat (non‐OR) binding sites. In order to gain insights into the structural determinants involved in PrPSc formation we investigated the effect of human PrPC (HuPrP) point mutations linked to the genetic form of human prion diseases. Previously, we carried out a structural investigation to determine the high resolution NMR structure of the truncated recHuPrP(90‐231) carrying the E219K polymorphism, the fCJD‐linked V210I and the GSS‐causing Q212P mutations. Such structural studies led to the preliminary conclusion that the structural disorder of the β2‐α2 loop region is a key pathological feature. Here, we evaluated the effect of the pathological mutations on the N‐terminal unstructured domain. We used synchrotron‐based X‐ray absorption structure (XAS) technique to study the coordination geometries of Cu(II) and Cu(I) at two pH values (5.5 and 7.0) in different recHuPrP(90‐231) constructs carrying pathological mutations. We clearly showed that mutations and pH exchanges cause a dramatic modification on both Cu(II) and Cu(I) coordinations in the non‐OR region. Our XAS study highlights the importance of the non‐OR region for prion conversion and proposes a cellular model in which PrPC coordinating copper with one His may be more prone to the conversion at acidic condition. Thus, the non‐OR region may act as the long‐sought‐after prion switch.