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

SummaryThe cellular prion protein PrPC 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 PrPC function and misfolding in disease. Here, we identify a Zn2+-driven N-terminal to C-terminal tertiary interaction in PrPC. 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 PrPC trafficking and control prion disease.

Graphical AbstractFigure optionsDownload high-quality image (72 K)Download as PowerPoint slideHighlights
► Zinc binds to the prion protein octarepeat domain
► The zinc-bound octarepeat makes a tertiary contact to C-terminal helices 2 and 3
► The encompassed surface carries a majority of the mutations in familial prion disease
► Familial mutations weaken this zinc-driven tertiary contact