title: Torsins: not your typical AAA+ ATPases.
abstract: Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that have led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.
authors.affiliation: a Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , CT , USA and.
authors.forename: April E
authors.initials: AE
authors.lastname: Rose
authors.affiliation: a Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , CT , USA and.
authors.forename: Rebecca S H
authors.initials: RS
authors.lastname: Brown
authors.affiliation: a Department of Molecular Biophysics and Biochemistry , Yale University , New Haven , CT , USA and.|b Department of Cell Biology , Yale School of Medicine , New Haven , CT , USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlieker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D021381:Protein Transport; D016415:Sequence Alignment
chemical_list: D002352:Carrier Proteins; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; C108175:TOR1A protein, human; C500006:TOR1AIP2 protein, human
keywords: Early-onset torsion dystonia; LAP1; LULL1; endoplasmic reticulum; nuclear envelope; torsinA