Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia
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 TorsinAE-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
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
- Wesley I Sundquist, University of Utah, United States
Version history
- Received: May 19, 2016
- Accepted: August 3, 2016
- Accepted Manuscript published: August 4, 2016 (version 1)
- Accepted Manuscript updated: August 17, 2016 (version 2)
- 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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