title: Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum.
abstract: TorsinA is a membrane-associated enzyme in the endoplasmic reticulum (ER) lumen that is mutated in DYT1 dystonia. How it remains in the ER has been unclear. We report that a hydrophobic N-terminal domain (NTD) directs static retention of torsinA within the ER by excluding it from ER exit sites, as has been previously reported for short transmembrane domains (TMDs). We show that despite the NTD's physicochemical similarity to TMDs, it does not traverse the membrane, defining torsinA as a lumenal monotopic membrane protein and requiring a new paradigm to explain retention. ER retention and membrane association are perturbed by a subset of nonconservative mutations to the NTD, suggesting that a helical structure with defined orientation in the membrane is required. TorsinA preferentially enriches in ER sheets, as might be expected for a lumenal monotopic membrane protein. We propose that the principle of membrane-based protein sorting extends to monotopic membrane proteins, and identify other proteins including the monotopic lumenal enzyme cyclooxygenase 1 (prostaglandin H synthase 1) that share this mechanism of retention with torsinA.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Vander Heyden
authors.forename: Teresa V
authors.initials: TV
authors.lastname: Naismith
authors.forename: Erik L
authors.initials: EL
authors.lastname: Snapp
authors.forename: Phyllis I
authors.initials: PI
authors.lastname: Hanson
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009685:Nuclear Envelope / Q000201:enzymology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; C108175:TOR1A protein, human; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human