Copper- and Zinc-Promoted Interdomain Structure in the Prion Protein: A Mechanism for Autoinhibition of the Neurotoxic N-Terminus

Abstract The function of the cellular prion protein (PrP C ), while still poorly understood, is increasingly linked to its ability to bind physiological metal ions at the cell surface. PrP C binds divalent forms of both copper and zinc through its unstructured N-terminal domain, modulating interactions between PrP C and various receptors at the cell surface and ultimately tuning downstream cellular processes. In this chapter, we briefly discuss the molecular features of copper and zinc uptake by PrP C and summarize evidence implicating these metal ions in PrP-mediated physiology. We then focus our review on recent biophysical evidence revealing a physical interaction between the flexible N-terminal and globular C-terminal domains of PrP C . This interdomain cis interaction is electrostatic in nature and is promoted by the binding of Cu 2 + and Zn 2 + to the N-terminal octarepeat domain. These findings, along with recent cellular studies, suggest a mechanism whereby N C interactions serve to regulate the activity and/or toxicity of the PrP C N-terminus. We discuss this potential mechanism in relation to familial prion disease mutations, lethal deletions of the PrP C central region, and neurotoxicity induced by certain globular domain ligands, including bona fide prions and toxic amyloid-β oligomers.