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.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: F Esra
authors.identifier: 0000-0002-3866-2742
authors.initials: FE
authors.lastname: Demircioglu
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Sosa
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ingram
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, United States.
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Thomas U
authors.identifier: 0000-0001-8012-1512
authors.initials: TU
authors.lastname: Schwartz
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020821:Dystonic Disorders / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C108175:TOR1A protein, human; C500006:TOR1AIP2 protein, human
keywords: AAA+ ATPases; biophysics; cell biology; dystonia; human; nuclear envelope; structural biology