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Title: 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 TorsinAΔE-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.

Authors:
ORCiD logo; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHERNIGMS
OSTI Identifier:
1314238
Resource Type:
Journal Article
Resource Relation:
Journal Name: eLife; Journal Volume: 5; Journal Issue: 2016
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Demircioglu, F. Esra, Sosa, Brian A., Ingram, Jessica, Ploegh, Hidde L., and Schwartz, Thomas U. Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. United States: N. p., 2016. Web. doi:10.7554/eLife.17983.
Demircioglu, F. Esra, Sosa, Brian A., Ingram, Jessica, Ploegh, Hidde L., & Schwartz, Thomas U. Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. United States. doi:10.7554/eLife.17983.
Demircioglu, F. Esra, Sosa, Brian A., Ingram, Jessica, Ploegh, Hidde L., and Schwartz, Thomas U. Thu . "Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia". United States. doi:10.7554/eLife.17983.
@article{osti_1314238,
title = {Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia},
author = {Demircioglu, F. Esra and Sosa, Brian A. and Ingram, Jessica and Ploegh, Hidde L. and Schwartz, Thomas U.},
abstractNote = {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 TorsinAΔE-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.},
doi = {10.7554/eLife.17983},
journal = {eLife},
number = 2016,
volume = 5,
place = {United States},
year = {Thu Aug 04 00:00:00 EDT 2016},
month = {Thu Aug 04 00:00:00 EDT 2016}
}