The N-terminus of the prion protein is a toxic effector regulated by the C-terminus
- Boston University School of Medicine, United States
- University of California, Davis, United States
- University of Delaware, United States
- Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Germany
- UC Santa Cruz, United States
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.
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Author details
Funding
National Institutes of Health (R01 NS065244)
- Bei Wu
- Alex McDonald
- Celeste B Rich
- David Harris
National Institutes of Health (R01 GM065790)
- Markham Kathleen
- Glenn L Millhauser
National Institutes of Health (GM104316)
- Kyle P Mchugh
- Colby David
National Science Foundation (Grant 1454508)
- Kyle P Mchugh
- Colby David
German Research Foundation ((TA 167/6))
- Jörg Tatzelt
N.I.H. R01 NS065244 to D.A.H had a role in study design, data collection and interpretation.N.I.H. R01 GM065790 to G.L.M. had a role in data collection.N.I.H. GM104316 to D.W.C. and N.S.F. grant 1454508 to D.W.C. had a role in data collection.German Research Foundation (TA 167/6) to J.T. had a role in data collection.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN14997) of Boston University.
Copyright
© 2017, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The N-terminus of the prion protein is a toxic effector regulated by the C-terminus
eLife 6:e23473.
https://doi.org/10.7554/eLife.23473
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