Jesús Tejero1, Alexandr A Kapralov2, Matthew P Baumgartner3, Courtney E Sparacino-Watkins4, Tamil S Anthonymutu5, Irina I Vlasova2, Carlos J Camacho6, Mark T Gladwin4, Hülya Bayir7, Valerian E Kagan8. 1. Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: jet68@pitt.edu. 2. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA. 3. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA. 4. Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. 5. Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15219, USA. 6. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: ccamacho@pitt.edu. 7. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: bayihx@ccm.upmc.edu. 8. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health and Center for Medical Countermeasures against Radiation, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: kagan@pitt.edu.
Abstract
Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The iron coordination and spin state of the Cygb heme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb's structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation. Thus, different anionic lipids can operate in cysteine-dependent and cysteine-independent ways as inducers of the peroxidase activity. We establish that Cygb's peroxidase activity can be utilized for the catalysis of peroxidation of anionic phospholipids (including phosphatidylinositolphosphates) yielding mono-oxygenated molecular species. Combined with the computational simulations we propose a bipartite lipid binding model that rationalizes the modes of interactions with phospholipids, the effects on structural re-arrangements and the peroxidase activity of the hemoprotein.
n class="Gene">Cytoglobin (Cygb) is a hexa-coordinated hemoprotein with yet to be defined physiological functions. The ironcoordination and spin state of the Cygbheme group are sensitive to oxidation of two cysteine residues (Cys38/Cys83) and/or the binding of free fatty acids. However, the roles of redox vs lipid regulators of Cygb's structural rearrangements in the context of the protein peroxidase competence are not known. Searching for physiologically relevant lipid regulators of Cygb, here we report that anionic phospholipids, particularly phosphatidylinositolphosphates, affect structural organization of the protein and modulate its iron state and peroxidase activity both conjointly and/or independently of cysteine oxidation. Thus, different anionic lipids can operate in cysteine-dependent and cysteine-independent ways as inducers of the peroxidase activity. We establish that Cygb's peroxidase activity can be utilized for the catalysis of peroxidation of anionic phospholipids (including phosphatidylinositolphosphates) yielding mono-oxygenated molecular species. Combined with the computational simulations we propose a bipartitelipid binding model that rationalizes the modes of interactions with phospholipids, the effects on structural re-arrangements and the peroxidase activity of the hemoprotein.
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