title: A ribosome-associating factor chaperones tail-anchored membrane proteins.
abstract: Hundreds of proteins are inserted post-translationally into the endoplasmic reticulum (ER) membrane by a single carboxy-terminal transmembrane domain (TMD). During targeting through the cytosol, the hydrophobic TMD of these tail-anchored (TA) proteins requires constant chaperoning to prevent aggregation or inappropriate interactions. A central component of this targeting system is TRC40, a conserved cytosolic factor that recognizes the TMD of TA proteins and delivers them to the ER for insertion. The mechanism that permits TRC40 to find and capture its TA protein cargos effectively in a highly crowded cytosol is unknown. Here we identify a conserved three-protein complex composed of Bat3, TRC35 and Ubl4A that facilitates TA protein capture by TRC40. This Bat3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the TMDs of newly released TA proteins, and transfers them to TRC40 for targeting. Depletion of the Bat3 complex allows non-TRC40 factors to compete for TA proteins, explaining their mislocalization in the analogous yeast deletion strains. Thus, the Bat3 complex acts as a TMD-selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway.
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Malaiyalam
authors.initials: M
authors.lastname: Mariappan
authors.forename: Xingzhe
authors.initials: X
authors.lastname: Li
authors.forename: Sandra
authors.initials: S
authors.lastname: Stefanovic
authors.forename: Ajay
authors.initials: A
authors.lastname: Sharma
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Mateja
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Keenan
authors.forename: Ramanujan S
authors.initials: RS
authors.lastname: Hegde
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D021381:Protein Transport; D012270:Ribosomes / Q000378:metabolism*; D018271:Signal Recognition Particle / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
chemical_list: C092009:BAG6 protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C480632:SRP54 protein, human; D018271:Signal Recognition Particle; D014452:Ubiquitins