Characterization of a reduced form of plasma plasminogen as the precursor for angiostatin formation.

The Journal of Biological Chemistry
Diego ButeraPhilip J Hogg

Abstract

Plasma plasminogen is the precursor of the tumor angiogenesis inhibitor, angiostatin. Generation of angiostatin in blood involves activation of plasminogen to the serine protease plasmin and facilitated cleavage of two disulfide bonds and up to three peptide bonds in the kringle 5 domain of the protein. The mechanism of reduction of the two allosteric disulfides has been explored in this study. Using thiol-alkylating agents, mass spectrometry, and an assay for angiostatin formation, we show that the Cys(462)-Cys(541) disulfide bond is already cleaved in a fraction of plasma plasminogen and that this reduced plasminogen is the precursor for angiostatin formation. From the crystal structure of plasminogen, we propose that plasmin ligands such as phosphoglycerate kinase induce a conformational change in reduced kringle 5 that leads to attack by the Cys(541) thiolate anion on the Cys(536) sulfur atom of the Cys(512)-Cys(536) disulfide bond, resulting in reduction of the bond by thiol/disulfide exchange. Cleavage of the Cys(512)-Cys(536) allosteric disulfide allows further conformational change and exposure of the peptide backbone to proteolysis and angiostatin release. The Cys(462)-Cys(541) and Cys(512)-Cys(536) disulfides have -/+...Continue Reading

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Citations

Oct 15, 2014·Antioxidants & Redox Signaling·Ronit Mor-Cohen
Aug 8, 2014·Biophysical Journal·Beifei ZhouFrauke Gräter
Feb 14, 2014·Blood·Diego ButeraPhilip J Hogg
Jan 12, 2017·Biophysical Journal·Beifei ZhouFrauke Gräter
Jun 23, 2018·ELife·Freda PassamPhilip J Hogg
Jan 13, 2019·The Journal of Biological Chemistry·Joyce Chiu, Philip J Hogg
Mar 9, 2018·Royal Society Open Science·Aster E PijningPhilip J Hogg
Jun 3, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Ankita SrivastavaAwanish Kumar

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