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.

Article and author information

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.

Metrics

  • 5,785
    views
  • 975
    downloads
  • 55
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2016)
Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function
eLife 5:e11184.
https://doi.org/10.7554/eLife.11184

Share this article

https://doi.org/10.7554/eLife.11184

Further reading

    1. Structural Biology and Molecular Biophysics
    Christopher T Schafer, Raymond F Pauszek III ... David P Millar
    Research Article

    The canonical chemokine receptor CXCR4 and atypical receptor ACKR3 both respond to CXCL12 but induce different effector responses to regulate cell migration. While CXCR4 couples to G proteins and directly promotes cell migration, ACKR3 is G-protein-independent and scavenges CXCL12 to regulate extracellular chemokine levels and maintain CXCR4 responsiveness, thereby indirectly influencing migration. The receptors also have distinct activation requirements. CXCR4 only responds to wild-type CXCL12 and is sensitive to mutation of the chemokine. By contrast, ACKR3 recruits GPCR kinases (GRKs) and β-arrestins and promiscuously responds to CXCL12, CXCL12 variants, other peptides and proteins, and is relatively insensitive to mutation. To investigate the role of conformational dynamics in the distinct pharmacological behaviors of CXCR4 and ACKR3, we employed single-molecule FRET to track discrete conformational states of the receptors in real-time. The data revealed that apo-CXCR4 preferentially populates a high-FRET inactive state, while apo-ACKR3 shows little conformational preference and high transition probabilities among multiple inactive, intermediate and active conformations, consistent with its propensity for activation. Multiple active-like ACKR3 conformations are populated in response to agonists, compared to the single CXCR4 active-state. This and the markedly different conformational landscapes of the receptors suggest that activation of ACKR3 may be achieved by a broader distribution of conformational states than CXCR4. Much of the conformational heterogeneity of ACKR3 is linked to a single residue that differs between ACKR3 and CXCR4. The dynamic properties of ACKR3 may underly its inability to form productive interactions with G proteins that would drive canonical GPCR signaling.

    1. Immunology and Inflammation
    2. Structural Biology and Molecular Biophysics
    Colleen A Maillie, Kiana Golden ... Marco Mravic
    Research Article

    A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside the epitope. We address the feasibility and determinant molecular features of this mechanism using multi-scale modeling. All-atom simulations of 4E10, PGZL1, 10E8, and LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining region loop sites, solidifying that stable and specific lipid interactions anchor bnAbs to membrane surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained simulations effectively capture antibodies embedding into membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved and correlates with neutralization potency. The modeling demonstrated here uncovers insights into lipid participation in antibodies’ recognition of membrane proteins and highlights antibody features to prioritize in vaccine design.