Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia
Name
Demircioglu-2016-Structures of Torsin.pdf
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1.95 MB
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Author(s)
Demircioglu, Fatma Esra
Ingram, Jessica
Ploegh, Hidde
Schwartz, Thomas
Sosa, Brian A.
Date Issued
August 2016
Journal
eLife
Publisher
eLife Sciences Publications, Ltd.
Citation
Demircioglu, F Esra et al. “Structures of TorsinA and Its Disease-Mutant Complexed with an Activator Reveal the Molecular Basis for Primary Dystonia.” eLife 5 (2016): n. pag.
Version
Final published version
Abstract
The most common cause of early onset primary dystonia, a neuromuscular disease, is a glutamate deletion (DE) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the DE 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 A˚ crystal structure of human TorsinA in complex with LULL1. This nanobody likewise stabilized the weakened TorsinADE-LULL1 interaction, which enabled us to solve its structure at 1.4 A˚ 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 TorsinADE could serve as a cure for primary dystonia.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.7554/eLife.17983
