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A substrate-driven allosteric switch that enhances PDI catalytic activity.

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.
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Contributor : Françoise DIGNAT-GEORGE Connect in order to contact the contributor
Submitted on : Monday, February 6, 2017 - 2:16:08 PM
Last modification on : Wednesday, November 3, 2021 - 9:47:38 AM


  • HAL Id : hal-01457378, version 1
  • PUBMED : 27573496



Roelof H Bekendam, Pavan K Bendapudi, Lin Lin, Partha P Nag, Jun Pu, et al.. A substrate-driven allosteric switch that enhances PDI catalytic activity.. Nature Communications, 2016, pp.12579. ⟨hal-01457378⟩



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