title: Structural basis of an ERAD pathway mediated by the ER-resident protein disulfide reductase ERdj5.
abstract: ER-associated degradation (ERAD) is an ER quality-control process that eliminates terminally misfolded proteins. ERdj5 was recently discovered to be a key ER-resident PDI family member protein that accelerates ERAD by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1. We here solved the crystal structure of full-length ERdj5, thereby revealing that ERdj5 contains the N-terminal J domain and six tandem thioredoxin domains that can be divided into the N- and C-terminal clusters. Our systematic biochemical analyses indicated that two thioredoxin domains that constitute the C-terminal cluster form the highly reducing platform that interacts with EDEM1 and reduces EDEM1-recruited substrates, leading to their facilitated degradation. The pulse-chase experiment further provided direct evidence for the sequential movement of an ERAD substrate from calnexin to the downstream EDEM1-ERdj5 complex, and then to the retrotranslocation channel, probably through BiP. We present a detailed molecular view of how ERdj5 mediates ERAD in concert with EDEM1.
authors.affiliation: Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Maegawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Ushioda
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Araki
authors.forename: Yushi
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Hoseki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Kenji
authors.initials: K
authors.lastname: Inaba
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011490:Protein Disulfide Reductase (Glutathione) / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D015398:Signal Transduction; D014162:Transfection
chemical_list: C471179:DNAJC10 protein, human; C486654:EDEM1 protein, human; C530517:ERdj5 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011490:Protein Disulfide Reductase (Glutathione)