title: Human Peroxin PEX3 Is Co-translationally Integrated into the ER and Exits the ER in Budding Vesicles.
abstract: The long-standing paradigm that all peroxisomal proteins are imported post-translationally into pre-existing peroxisomes has been challenged by the detection of peroxisomal membrane proteins (PMPs) inside the endoplasmic reticulum (ER). In mammals, the mechanisms of ER entry and exit of PMPs are completely unknown. We show that the human PMP PEX3 inserts co-translationally into the mammalian ER via the Sec61 translocon. Photocrosslinking and fluorescence spectroscopy studies demonstrate that the N-terminal transmembrane segment (TMS) of ribosome-bound PEX3 is recognized by the signal recognition particle (SRP). Binding to SRP is a prerequisite for targeting of the PEX3-containing ribosome•nascent chain complex (RNC) to the translocon, where an ordered multistep pathway integrates the nascent chain into the membrane adjacent to translocon proteins Sec61α and TRAM. This insertion of PEX3 into the ER is physiologically relevant because PEX3 then exits the ER via budding vesicles in an ATP-dependent process. This study identifies early steps in human peroxisomal biogenesis by demonstrating sequential stages of PMP passage through the mammalian ER.
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, 440 Reynolds Medical Building, College Station, TX, 77843, USA.|Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438, Frankfurt, Germany.|Present address: School of Biosciences & Medicine, University of Surrey, Guildford, GU2 7XH, UK.
authors.forename: Peter U
authors.initials: PU
authors.lastname: Mayerhofer
authors.affiliation: Departament de Bioquimica i Biologia Molecular, Universitat de Valencia, C/ Dr. Moliner, 50, E-46100, Burjassot, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bañó-Polo
authors.affiliation: Departament de Bioquimica i Biologia Molecular, Universitat de Valencia, C/ Dr. Moliner, 50, E-46100, Burjassot, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Mingarro
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, 440 Reynolds Medical Building, College Station, TX, 77843, USA.|Department of Chemistry, Texas A&M University, College Station, TX, 77843, USA.|Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, 77843, USA.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Johnson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D000074401:Peroxins; D020675:Peroxisomes / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D012270:Ribosomes / Q000378:metabolism; D018271:Signal Recognition Particle / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008074:Lipoproteins; D008565:Membrane Proteins; D000074401:Peroxins; C113138:Pex3 protein, human; D018271:Signal Recognition Particle; C480228:TICAM2 protein, human
keywords: Sec61 translocon; budding vesicles; endoplasmic reticulum; human peroxisomal membrane protein PEX3; peroxisomal biogenesis