A substrate-driven allosteric switch that enhances PDI catalytic activity

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 and Robert Flaumenhaft ()
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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
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
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
Robert Flaumenhaft: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12579

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