title: Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface.
abstract: 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 Zn²⁺-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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Ann R
authors.initials: AR
authors.lastname: Spevacek
authors.forename: Eric G B
authors.initials: EG
authors.lastname: Evans
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Miller
authors.forename: Heidi C
authors.initials: HC
authors.lastname: Meyer
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Pelton
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D015032:Zinc / Q000737:chemistry*
chemical_list: D018621:PrPC Proteins; D015032:Zinc