A substrate-driven allosteric switch that enhances PDI catalytic activity

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A substrate-driven allosteric switch that enhances PDI catalytic activity

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Title: A substrate-driven allosteric switch that enhances PDI catalytic activity
Author: 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

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Citation: Bekendam, R. H., P. K. Bendapudi, L. Lin, P. P. Nag, J. Pu, D. R. Kennedy, A. Feldenzer, et al. 2016. “A substrate-driven allosteric switch that enhances PDI catalytic activity.” Nature Communications 7 (1): 12579. doi:10.1038/ncomms12579. http://dx.doi.org/10.1038/ncomms12579.
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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.
Published Version: doi:10.1038/ncomms12579
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013553/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29407554
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