Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

  1. Ravi Vijayvargia
  2. Raquel Epand
  3. Alexander Leitner
  4. Tae-Yang Jung
  5. Baehyun Shin
  6. Roy Jung
  7. Alejandro Lloret
  8. Randy Singh Atwal
  9. Hyeongseok Lee
  10. Jong-Min Lee
  11. Ruedi Aebersold
  12. Hans Hebert
  13. Ji-Joon Song
  14. Ihn Sik Seong  Is a corresponding author
  1. The Maharaja Sayajirao University of Baroda, India
  2. McMaster University, Canada
  3. Eidgenössische Technische Hochschule Zürich, Switzerland
  4. Korea Advanced Institute of Science and Technology, Republic of Korea
  5. Massachusetts General Hospital, United States
  6. Universidad Autónoma de Querétaro, Mexico
  7. Karolinska Institute, Sweden

Abstract

The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single-particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical α-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly we showed that the polyglutamine expansion increases α-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease.

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Author details

  1. Ravi Vijayvargia

    Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Raquel Epand

    Biochemical ad Biomedical Sciences, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexander Leitner

    Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Tae-Yang Jung

    Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Baehyun Shin

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Roy Jung

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alejandro Lloret

    Facultad de Medicina, Universidad Autónoma de Querétaro, Santiago de Querétaro, Mexico
    Competing interests
    The authors declare that no competing interests exist.
  8. Randy Singh Atwal

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Hyeongseok Lee

    Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Jong-Min Lee

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ruedi Aebersold

    Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Hans Hebert

    Department of Biosciences and Nutrition, Karolinska Institute, Solna, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  13. Ji-Joon Song

    Department of Biological Sciences, Cancer Metastasis Control Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  14. Ihn Sik Seong

    Center for Human Genetic Research, Massachusetts General Hospital, Boston, United States
    For correspondence
    iseong@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2016, Vijayvargia 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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