UC Santa Cruz

The prion protein (PrP) is the causative agent for a class of fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). This highly conserved mammalian protein consists of two domains - a flexible N-terminus, which is implicated in PrP's biological function; and a structured C-terminus that misfolds to create the infectious agent. Decades of research have determined that PrP binds copper and zinc and therefore contributes to metal ion homeostasis. The role of these metal ions in TSE progression, however, is still unclear. To clarify whether Cu2+ has a direct influence on the misfolding of PrP's structured domain, we assess the affinity of the C-terminal histidines for copper. Our results show that this metal ion does not bind to PrP's C-terminus with a physiologically relevant affinity. This work also challenges the notion that PrP's two domains are physically independent. We identify here a novel Zn2+-driven inter-domain interaction in PrP. The docking site of the Zn2+-bound N-terminus is localized to a region of the C-terminus that contains the majority of the inherited mutations that give rise to familial prion disease. We therefore investigated the affect of these mutations, as well as a mutation protective against prion disease, on the inter-domain interaction. We find that the pathogenic mutations exhibit a weakened inter-domain interaction, whereas the protective mutant has a strengthen interaction as compared to wild type PrP. These results provide the first evidence of a change in the tertiary structure of PrP that correlates with the familial prion disease mutations. Furthermore, these results provide new structural insight into PrP's biological processing and function.