The Highly Dynamic Nature of ERdj5 Is Key to Efficient Elimination of Aberrant Protein Oligomers through ER-Associated Degradation

Ken ichi Maegawa, Satoshi Watanabe, Kentaro Noi, Masaki Okumura, Yuta Amagai, Michio Inoue, Ryo Ushioda, Kazuhiro Nagata, Teru Ogura, Kenji Inaba

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

ERdj5, composed of an N-terminal J domain followed by six thioredoxin-like domains, is the largest protein disulfide isomerase family member and functions as an ER-localized disulfide reductase that enhances ER-associated degradation (ERAD). Our previous studies indicated that ERdj5 comprises two regions, the N- and C-terminal clusters, separated by a linker loop and with distinct functional roles in ERAD. We here present a new crystal structure of ERdj5 with a largely different cluster arrangement relative to that in the original crystal structure. Single-molecule observation by high-speed atomic force microscopy visualized rapid cluster movement around the flexible linker loop, indicating the highly dynamic nature of ERdj5 in solution. ERdj5 mutants with a fixed-cluster orientation compromised the ERAD enhancement activity, likely because of less-efficient reduction of aberrantly formed disulfide bonds and prevented substrate transfer in the ERdj5-mediated ERAD pathway. We propose a significant role of ERdj5 conformational dynamics in ERAD of disulfide-linked oligomers.

Original languageEnglish
Pages (from-to)846-857.e4
JournalStructure
Volume25
Issue number6
DOIs
Publication statusPublished - 2017 Jun 6

Keywords

  • ERAD
  • ERdj5
  • X-ray crystal structure analysis
  • high-speed AFM
  • single-molecule analysis

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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