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

Autor:	Bekendam RH; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA., Bendapudi PK; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA., Lin L; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA., Nag PP; Department of Pharmaceutical and Administrative Sciences, The Broad Institute Probe Development Center, Cambridge, Massachusetts 02142, USA.; Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts 02142, USA., Pu J; Department of Pharmaceutical and Administrative Sciences, The Broad Institute Probe Development Center, Cambridge, Massachusetts 02142, USA., Kennedy DR; College of Pharmacy, Western New England University, Springfield, Massachusetts 01119, USA., Feldenzer A; College of Pharmacy, Western New England University, Springfield, Massachusetts 01119, USA., Chiu J; The Centenary Institute, Newtown, Sydney, New South Wales 2050, Australia.; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales 2050, Australia., Cook KM; The Centenary Institute, Newtown, Sydney, New South Wales 2050, Australia., Furie B; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA., Huang M; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA., Hogg PJ; The Centenary Institute, Newtown, Sydney, New South Wales 2050, Australia.; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, New South Wales 2050, Australia., Flaumenhaft R; Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2016 Aug 30; Vol. 7, pp. 12579. Date of Electronic Publication: 2016 Aug 30.
DOI:	10.1038/ncomms12579
Abstrakt:	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. Competing Interests: R.F. and P.P.N. are co-inventors on pending patents describing bepristats 1 and 2. The remaining authors declare no competing financial interests.
Databáze:	MEDLINE
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