Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia

  1. F Esra Demircioglu
  2. Brian A Sosa
  3. Jessica Ingram
  4. Hidde L Ploegh
  5. Thomas U Schwartz  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
  2. Whitehead Institute for Biomedical Research, United States

Abstract

The most common cause of early onset primary dystonia, a neuromuscular disease, is a glutamate deletion (ΔE) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the ΔE mutation is known to diminish binding of two TorsinA ATPase activators: lamina-associated protein 1 (LAP1) and its paralog, luminal domain like LAP1 (LULL1). Using a nanobody as a crystallization chaperone, we obtained a 1.4 Å crystal structure of human TorsinA in complex with LULL1. This nanobody likewise stabilized the weakened TorsinAE-LULL1 interaction, which enabled us to solve its structure at 1.4 Å also. A comparison of these structures shows, in atomic detail, the subtle differences in activator interactions that separate the healthy from the diseased state. This information may provide a structural platform for drug development, as a small molecule that rescues TorsinAΔE could serve as a cure for primary dystonia.

Article and author information

Author details

  1. F Esra Demircioglu

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    F Esra Demircioglu, Filed a provisional patent application protecting the use of the crystal structures (U.S.P.T.O. No. 62/330,683).
  2. Brian A Sosa

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    Brian A Sosa, Filed a provisional patent application protecting the use of the crystal structures (U.S.P.T.O. No. 62/330,683).
  3. Jessica Ingram

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Hidde L Ploegh

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Thomas U Schwartz

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    tus@mit.edu
    Competing interests
    Thomas U Schwartz, Filed a provisional patent application protecting the use of the crystal structures (U.S.P.T.O. No. 62/330,683).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8012-1512

Funding

Foundation for Dystonia Research

  • Thomas U Schwartz

National Institutes of Health

  • Thomas U Schwartz

National Institutes of Health

  • Hidde L Ploegh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Wesley I Sundquist, University of Utah, United States

Version history

  1. Received: May 19, 2016
  2. Accepted: August 3, 2016
  3. Accepted Manuscript published: August 4, 2016 (version 1)
  4. Accepted Manuscript updated: August 17, 2016 (version 2)
  5. Version of Record published: August 25, 2016 (version 3)

Copyright

© 2016, Demircioglu 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. F Esra Demircioglu
  2. Brian A Sosa
  3. Jessica Ingram
  4. Hidde L Ploegh
  5. Thomas U Schwartz
(2016)
Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia
eLife 5:e17983.
https://doi.org/10.7554/eLife.17983

Share this article

https://doi.org/10.7554/eLife.17983

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