Structural Basis of an ERAD Pathway Mediated by the ER-Resident Protein Disulfide Reductase ERdj5

• Hagiwara, Masatoshi

  Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University

• Maegawa, Ken-ichi

  2Division of Protein Chemistry, Post-Genome Science Center, Medical Institute of Bioregulation, Kyushu University

• Suzuki, Mamoru

  Institute for Protein Research, Osaka University

• Ushioda, Ryo

  Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University | Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University

• Araki, Kazutaka

  Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University

• Matsumoto, Yushi

  2Division of Protein Chemistry, Post-Genome Science Center, Medical Institute of Bioregulation, Kyushu University

• Hoseki, Jun

  Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University | Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University

• Nagata, Kazuhiro

  Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University | Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University

• Inaba, Kenji

  2Division of Protein Chemistry, Post-Genome Science Center, Medical Institute of Bioregulation, Kyushu University

Abstract

ER-associated degradation (ERAD) is an ER qualitycontrol 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.

Journal

• Molecular Cell

  Molecular Cell 41 (4), 432-444, 2011-02-18

  Elsevier

Keywords

• ER-associated degradation
• ERAD
• ERdj5
• EDEM1

Details

• CRID: 1050298532705062912
• NII Article ID: 120003836694
• NII Book ID: AA1119005X
• DOI: 10.1016/j.molcel.2011.01.021
• HANDLE: 2324/19148
• ISSN: 10972765
• Web Site: https://api.elsevier.com/content/article/PII:S1097276511000487?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S1097276511000487?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
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