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.
- Authors:
-
- Harvard Medical School, Boston, MA (United States). Div. of Hemostasis and Thrombosis, Dept. of Medicine, Beth Israel Deaconess Medical Center
- The Broad Institute Probe Development Center, Cambridge, MA (United States). Department of Pharmaceutical and Administrative Sciences; Center for the Science of Therapeutics, Broad Institute, Cambridge, MA (United States)
- The Broad Institute Probe Development Center, Cambridge, MA (United States). Dept. of Pharmaceutical and Administrative Sciences
- Western New England Univ., Springfield, MA (United States). College of Pharmacy
- The Centenary Institute, Newtown, Sydney, New South Wales, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
- The Centenary Institute, Newtown, Sydney, New South Wales, Australia
- The Centenary Institute, Newtown, 2050, Sydney, New South Wales, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, 2050, New South Wales, Australia
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI); National Institute on Drug Abuse (NIDA); NIH Molecular Libraries Probe Production Centers Network (MLPCN); Hemostasis and Thrombosis Research Society
- OSTI Identifier:
- 1623845
- Grant/Contract Number:
- AC02-05CH11231; U54 HL112302; R01 HL125275; R01 HL112809; T32 HL007917; T32 HL16324-02; HL116324; DA032476; U54 HG005032
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- Science & Technology - Other Topics
Citation Formats
Bekendam, Roelof H., Bendapudi, Pavan K., Lin, Lin, Nag, Partha P., Pu, Jun, Kennedy, Daniel R., Feldenzer, Alexandra, Chiu, Joyce, Cook, Kristina M., Furie, Bruce, Huang, Mingdong, Hogg, Philip J., and Flaumenhaft, Robert. A substrate-driven allosteric switch that enhances PDI catalytic activity. United States: N. p., 2016.
Web. doi:10.1038/ncomms12579.
Bekendam, Roelof H., Bendapudi, Pavan K., Lin, Lin, Nag, Partha P., Pu, Jun, Kennedy, Daniel R., Feldenzer, Alexandra, Chiu, Joyce, Cook, Kristina M., Furie, Bruce, Huang, Mingdong, Hogg, Philip J., & Flaumenhaft, Robert. A substrate-driven allosteric switch that enhances PDI catalytic activity. United States. https://doi.org/10.1038/ncomms12579
Bekendam, Roelof H., Bendapudi, Pavan K., Lin, Lin, Nag, Partha P., Pu, Jun, Kennedy, Daniel R., Feldenzer, Alexandra, Chiu, Joyce, Cook, Kristina M., Furie, Bruce, Huang, Mingdong, Hogg, Philip J., and Flaumenhaft, Robert. Tue .
"A substrate-driven allosteric switch that enhances PDI catalytic activity". United States. https://doi.org/10.1038/ncomms12579. https://www.osti.gov/servlets/purl/1623845.
@article{osti_1623845,
title = {A substrate-driven allosteric switch that enhances PDI catalytic activity},
author = {Bekendam, Roelof H. and Bendapudi, Pavan K. and Lin, Lin and Nag, Partha P. and Pu, Jun and Kennedy, Daniel R. and Feldenzer, Alexandra and Chiu, Joyce and Cook, Kristina M. and Furie, Bruce and Huang, Mingdong and Hogg, Philip J. and Flaumenhaft, Robert},
abstractNote = {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.},
doi = {10.1038/ncomms12579},
journal = {Nature Communications},
number = 1,
volume = 7,
place = {United States},
year = {Tue Aug 30 00:00:00 EDT 2016},
month = {Tue Aug 30 00:00:00 EDT 2016}
}
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