A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization

Masaki Okumura, Shingo Kanemura, Motonori Matsusaki, Misaki Kinoshita, Tomohide Saio, Dai Ito, Chihiro Hirayama, Hiroyuki Kumeta, Mai Watabe, Yuta Amagai, Young Ho Lee, Shuji Akiyama, Kenji Inaba

Research output: Contribution to journalArticlepeer-review

Abstract

P5, also known as PDIA6, is a PDI family member involved in the ER quality control. Here, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. Unlike conventional leucine zipper motifs with leucine residues every two helical turns on ∼30-residue parallel α helices, this adhesive motif includes periodic repeats of leucine/valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α helices. The P5 dimerization interface is further stabilized by several reciprocal salt bridges and C-capping interactions between protomers. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as aberrant proteins that induce the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via intermolecular disulfide bond reduction and its Ca2+-dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and function of P5.

Original languageEnglish
JournalStructure
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • ER quality control
  • NMR
  • P5
  • SAXS
  • calcium binding
  • dimerization motif
  • oxidative protein folding
  • protein disulfide isomerase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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