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

ELife
Bei WuDavid A Harris

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 PrPCfunctions as a powerful toxicity-transducing effector whose activity is tightly regulatedin cisby 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.

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Citations

Apr 11, 2018·The Journal of Biological Chemistry·Anna D EngelkeJörg Tatzelt
Sep 30, 2017·Prion·Alex J McDonaldDavid A Harris
Dec 28, 2018·Brain Pathology·Nhat T T LeDavid A Harris
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Nov 23, 2021·Journal of Molecular Biology·Aishwarya Agarwal, Samrat Mukhopadhyay
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Methods Mentioned

BETA
NMR
fluorescence microscopy
Fluorescence
restriction digest
fluorescence-activated cell sorting
transfection

Software Mentioned

Sparky
CcpNmr Analysis
Sparky NMR Analysis
NMRDraw
PClamp
Kaleidagraph
CcpNmr
NMRPipe
Synergy

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