title: The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein.
abstract: A glutamic acid deletion (DeltaE) in the AAA+ protein torsinA causes DYT1 dystonia. Although the majority of torsinA resides within the endoplasmic reticulum (ER), torsinA binds a substrate in the lumen of the nuclear envelope (NE), and the DeltaE mutation enhances this interaction. Using a novel cell-based screen, we identify lamina-associated polypeptide 1 (LAP1) as a torsinA-interacting protein. LAP1 may be a torsinA substrate, as expression of the isolated lumenal domain of LAP1 inhibits the NE localization of "substrate trap" EQ-torsinA and EQ-torsinA coimmunoprecipitates with LAP1 to a greater extent than wild-type torsinA. Furthermore, we identify a novel transmembrane protein, lumenal domain like LAP1 (LULL1), which also appears to interact with torsinA. Interestingly, LULL1 resides in the main ER. Consequently, torsinA interacts directly or indirectly with a novel class of transmembrane proteins that are localized in different subdomains of the ER system, either or both of which may play a role in the pathogenesis of DYT1 dystonia.
authors.affiliation: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Goodchild
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D049452:Green Fluorescent Proteins / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D009685:Nuclear Envelope / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C494372:Hspa8 protein, mouse; C000608254:LAP1 protein, mouse; C000608255:LULL1 protein, mouse; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011506:Proteins; C108175:TOR1A protein, human; C500006:TOR1AIP2 protein, human; D049452:Green Fluorescent Proteins