Dynamic assembly of protein disulfide isomerase in catalysis of oxidative folding

Masaki Okumura, Kentaro Noi, Shingo Kanemura, Misaki Kinoshita, Tomohide Saio, Yuichi Inoue, Takaaki Hikima, Shuji Akiyama, Teru Ogura, Kenji Inaba

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Time-resolved direct observations of proteins in action provide essential mechanistic insights into biological processes. Here, we present mechanisms of action of protein disulfide isomerase (PDI)—the most versatile disulfide-introducing enzyme in the endoplasmic reticulum—during the catalysis of oxidative protein folding. Single-molecule analysis by high-speed atomic force microscopy revealed that oxidized PDI is in rapid equilibrium between open and closed conformations, whereas reduced PDI is maintained in the closed state. In the presence of unfolded substrates, oxidized PDI, but not reduced PDI, assembles to form a face-to-face dimer, creating a central hydrophobic cavity with multiple redox-active sites, where substrates are likely accommodated to undergo accelerated oxidative folding. Such PDI dimers are diverse in shape and have different lifetimes depending on substrates. To effectively guide proper oxidative protein folding, PDI regulates conformational dynamics and oligomeric states in accordance with its own redox state and the configurations or folding states of substrates.

Original languageEnglish
Pages (from-to)499-509
Number of pages11
JournalNature Chemical Biology
Issue number5
Publication statusPublished - 2019 May 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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