The N-terminus of the prion protein is a toxic effector regulated by the C-terminus

Elife. 2017 May 20:6:e23473. doi: 10.7554/eLife.23473.

Abstract

PrPC, the cellular isoform of the prion protein, serves to transduce the neurotoxic effects of PrPSc, 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 PrPC functions as a powerful toxicity-transducing effector whose activity is tightly regulated in cis 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 PrPC, revealing a novel auto-inhibitory mechanism that regulates the functional activity of PrPC.

Keywords: mouse; neuroscience; neurotoxicity; prion; protein regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dendrites / pathology
  • Hippocampus / pathology
  • Homeostasis*
  • Magnetic Resonance Spectroscopy
  • Mice
  • Neurons / pathology
  • PrPC Proteins / chemistry
  • PrPC Proteins / toxicity*
  • Prion Proteins / chemistry
  • Prion Proteins / toxicity*
  • Protein Conformation

Substances

  • PrPC Proteins
  • Prion Proteins
  • Prnp protein, mouse