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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 (?E) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the ?E 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 TorsinA?E could serve as a cure for primary dystonia.

SUBMITTER: Demircioglu FE

PROVIDER: S-EPMC4999309 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Demircioglu F Esra FE Sosa Brian A BA Ingram Jessica J Ploegh Hidde L HL Schwartz Thomas U TU

eLife 20160804

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 ...[more]

PMID: 27490483

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Project description:Dystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (?GAG) deletion that results in the loss of a glutamic acid residue (?E302/303) in the carboxyl terminal region of torsinA. This torsinA?E mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine. Here, we demonstrate that human torsinA?E dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinA?E were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinA?E inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila Dtorsin?E equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinA?E and Dtorsin?E act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.

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

Publications

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

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