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A substrate-driven allosteric switch that enhances PDI catalytic activity

Author

Listed:
  • Roelof H. Bekendam

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Pavan K. Bendapudi

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Lin Lin

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Partha P. Nag

    (The Broad Institute Probe Development Center
    Center for the Science of Therapeutics, Broad Institute)

  • Jun Pu

    (The Broad Institute Probe Development Center)

  • Daniel R. Kennedy

    (College of Pharmacy, Western New England University)

  • Alexandra Feldenzer

    (College of Pharmacy, Western New England University)

  • Joyce Chiu

    (The Centenary Institute
    National Health and Medical Research Council Clinical Trials Centre, University of Sydney)

  • Kristina M. Cook

    (The Centenary Institute)

  • Bruce Furie

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Mingdong Huang

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Philip J. Hogg

    (The Centenary Institute
    National Health and Medical Research Council Clinical Trials Centre, University of Sydney)

  • Robert Flaumenhaft

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

Abstract

Protein disulfide isomerase (PDI) is an oxidoreductase essential for folding proteins in the endoplasmic reticulum. The domain structure of PDI is a–b–b′–x–a′, wherein the thioredoxin-like a and a′ domains mediate disulfide bond shuffling and b and b′ domains are substrate binding. The b′ and a′ domains are connected via the x-linker, a 19-amino-acid flexible peptide. Here we identify a class of compounds, termed bepristats, that target the substrate-binding pocket of b′. Bepristats reversibly block substrate binding and inhibit platelet aggregation and thrombus formation in vivo. Ligation of the substrate-binding pocket by bepristats paradoxically enhances catalytic activity of a and a′ by displacing the x-linker, which acts as an allosteric switch to augment reductase activity in the catalytic domains. This substrate-driven allosteric switch is also activated by peptides and proteins and is present in other thiol isomerases. Our results demonstrate a mechanism whereby binding of a substrate to thiol isomerases enhances catalytic activity of remote domains.

Suggested Citation

  • Roelof H. Bekendam & Pavan K. Bendapudi & Lin Lin & Partha P. Nag & Jun Pu & Daniel R. Kennedy & Alexandra Feldenzer & Joyce Chiu & Kristina M. Cook & Bruce Furie & Mingdong Huang & Philip J. Hogg & R, 2016. "A substrate-driven allosteric switch that enhances PDI catalytic activity," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12579
    DOI: 10.1038/ncomms12579
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    Cited by:

    1. Keyu Lv & Shuai Chen & Xulin Xu & Joyce Chiu & Haoqing J. Wang & Yunyun Han & Xiaodan Yang & Sheryl R. Bowley & Hao Wang & Zhaoming Tang & Ning Tang & Aizhen Yang & Shuofei Yang & Jinyu Wang & Si Jin , 2024. "Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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