The N-terminus of the Prion Protein is a Toxic Effector Regulated by the C-terminus

Overview

Journal Elife

Specialty Biology

Date 2017 May 21

PMID 28527237

Citations 40

Authors

Bei Wu

Alex J McDonald

Kathleen Markham

Celeste B Rich

Kyle P McHugh

Jorg Tatzelt

David W Colby

Glenn L Millhauser

David A Harris

Affiliations

Soon will be listed here.

Abstract

PrP, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrP, the infectious isoform, but how this occurs is mysterious. Here, using a combination of electrophysiological, cellular, and biophysical techniques, we show that the flexible, N-terminal domain of PrP functions as a powerful toxicity-transducing effector whose activity is tightly regulated by the globular C-terminal domain. Ligands binding to the N-terminal domain abolish the spontaneous ionic currents associated with neurotoxic mutants of PrP, and the isolated N-terminal domain induces currents when expressed in the absence of the C-terminal domain. Anti-PrP antibodies targeting epitopes in the C-terminal domain induce currents, and cause degeneration of dendrites on murine hippocampal neurons, effects that entirely dependent on the effector function of the N-terminus. NMR experiments demonstrate intramolecular docking between N- and C-terminal domains of PrP, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrP.

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