Zinc Drives a Tertiary Fold in the Prion Protein with Familial Disease Mutation Sites at the Interface

Summary The cellular prion protein PrP C consists of two domains—a flexible N-terminal domain, which participates in copper and zinc regulation, and a largely helical C-terminal domain that converts to β sheet in the course of prion disease. These two domains are thought to be fully independent and noninteracting. Compelling cellular and biophysical studies, however, suggest a higher order structure that is relevant to both PrP C function and misfolding in disease. Here, we identify a Zn 2+ -driven N-terminal to C-terminal tertiary interaction in PrP C . The C-terminal surface participating in this interaction carries the majority of the point mutations that confer familial prion disease. Investigation of mutant PrPs finds a systematic relationship between the type of mutation and the apparent strength of this domain structure. The structural features identified here suggest mechanisms by which physiologic metal ions trigger PrP C trafficking and control prion disease.