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 (PrPC), while still poorly understood, is increasingly linked to its ability to bind physiological metal ions at the cell surface. PrPC binds divalent forms of both copper and zinc through its unstructured N-terminal domain, modulating interactions between PrPC 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 PrPC 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 PrPC. This interdomain cis interaction is electrostatic in nature and is promoted by the binding of Cu2+ and Zn2+ to the N-terminal octarepeat domain. These findings, along with recent cellular studies, suggest a mechanism whereby NC interactions serve to regulate the activity and/or toxicity of the PrPC N-terminus. We discuss this potential mechanism in relation to familial prion disease mutations, lethal deletions of the PrPC central region, and neurotoxicity induced by certain globular domain ligands, including bona fide prions and toxic amyloid-β oligomers.