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

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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.

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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).
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).
Jessica Ingram

Whitehead Institute for Biomedical Research, Cambridge, United States

Competing interests
No competing interests declared.
Hidde L Ploegh

Whitehead Institute for Biomedical Research, Cambridge, United States

Competing interests
No competing interests declared.
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).

"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.

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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.