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

  1. Bei Wu
  2. Alex J McDonald
  3. Kathleen Markham
  4. Celeste B Rich
  5. Kyle P Mchugh
  6. Jörg Tatzelt
  7. David W Colby
  8. Glenn L Millhauser
  9. David A Harris  Is a corresponding author
  1. Boston University School of Medicine, United States
  2. University of California, Davis, United States
  3. University of Delaware, United States
  4. Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Germany
  5. 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.

Article and author information

Author details

  1. Bei Wu

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alex J McDonald

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kathleen Markham

    Department of Chemistry and Biochemistry, University of California, Davis, Santa Cruz, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Celeste B Rich

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kyle P Mchugh

    Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jörg Tatzelt

    Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5017-5528
  7. David W Colby

    Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Glenn L Millhauser

    Department of Chemistry, UC Santa Cruz, Santa Cruz, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. David A Harris

    Department of Biochemistry, Boston University School of Medicine, Boston, United States
    For correspondence
    daharris@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6985-5790

Funding

National Institutes of Health (R01 NS065244)

  • Bei Wu
  • Alex J McDonald
  • Celeste B Rich
  • David A Harris

National Institutes of Health (R01 GM065790)

  • Kathleen Markham
  • Glenn L Millhauser

National Institutes of Health (GM104316)

  • Kyle P Mchugh
  • David W Colby

National Science Foundation (Grant 1454508)

  • Kyle P Mchugh
  • David W Colby

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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  1. Bei Wu
  2. Alex J McDonald
  3. Kathleen Markham
  4. Celeste B Rich
  5. Kyle P Mchugh
  6. Jörg Tatzelt
  7. David W Colby
  8. Glenn L Millhauser
  9. David A Harris
(2017)
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

Share this article

https://doi.org/10.7554/eLife.23473

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