title: Regulation of Torsin ATPases by LAP1 and LULL1.
abstract: TorsinA is a membrane-associated AAA+ (ATPases associated with a variety of cellular activities) ATPase implicated in primary dystonia, an autosomal-dominant movement disorder. We reconstituted TorsinA and its cofactors in vitro and show that TorsinA does not display ATPase activity in isolation; ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. This interaction requires TorsinA to be in the ATP-bound state, and can be attributed to the luminal domains of LAP1 and LULL1. This ATPase activator function controls the activities of other members of the Torsin family in distinct fashion, leading to an acceleration of the hydrolysis step by up to two orders of magnitude. The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Rebecca S H
authors.initials: RS
authors.lastname: Brown
authors.forename: Anna R
authors.initials: AR
authors.lastname: Chase
authors.forename: Markus R
authors.initials: MR
authors.lastname: Eisele
authors.forename: Christian
authors.initials: C
authors.lastname: Schlieker
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D015151:Immunoblotting; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*
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; D000251:Adenosine Triphosphatases