Non-covalent and covalent modifications modulate the reactivity of monomeric mammalian globins |
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| Authors: | Paolo Ascenzi Maria Marino Fabio Polticelli Massimo Coletta Magda Gioia Stefano Marini Alessandra Pesce Marco Nardini Martino Bolognesi Brandon J. Reeder Michael T. Wilson |
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| Affiliation: | 1. Interdepartmental Laboratory of Electron Microscopy, University Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy;2. National Institute of Biostructures and Biosystems, Viale Medaglie d''Oro 305, I-00136 Roma, Italy;3. Department of Sciences, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy;4. Department of Clinical Sciences and Translational Medicine, University of Roma “Tor Vergata”, Via Montpellier 1, I-00133 Roma, Italy;5. Interuniversity Consortium for the Research on the Chemistry of Metals in Biological Systems, Via Celso Ulpiani 27, I-70126 Bari, Italy;6. Department of Physics, University of Genova, Via Dodecaneso 33, I-16146 Genova, Italy;g Department of Biosciences, University of Milano, Via Celoria 26, I-20133 Milano, Italy;h Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK |
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| Abstract: | Multimeric globins (e.g., hemoglobin) are considered to be the prototypes of allosteric enzymes, whereas monomeric globins (e.g., myoglobin; Mb) usually are assumed to be non-allosteric. However, the modulation of the functional properties of monomeric globins by non-covalent (or allosteric) and covalent modifications casts doubts on this general assumption. Here, we report examples referable to these two extreme mechanisms modulating the reactivity of three mammalian monomeric globins. Sperm whale Mb, which acts as a reserve supply of O2 and facilitates the O2 flux within a myocyte, displays the allosteric modulation of the O2 affinity on lactate, an obligatory product of glycolysis under anaerobic conditions, thus facilitating O2 diffusion to the mitochondria in supporting oxidative phosphorylation. Human neuroglobin (NGB), which appears to protect neurons from hypoxia in vitro and in vivo, undergoes hypoxia-dependent phosphorylation (i.e., covalent modulation) affecting the coordination equilibrium of the heme-Fe atom and, in turn, the heme-protein reactivity. This facilitates heme-Fe-ligand binding and enhances the rate of anaerobic nitrite reduction to form NO, thus contributing to cellular adaptation to hypoxia. The reactivity of human cytoglobin (CYGB), which has been postulated to protect cells against oxidative stress, depends on both non-covalent and covalent mechanisms. In fact, the heme reactivity of CYGB depends on the lipid, such as oleate, binding which stabilizes the penta-coordination geometry of the heme-Fe atom. Lastly, the reactivity of NGB and CYGB is modulated by the redox state of the intramolecular CysCD7/CysD5 and CysB2/CysE9 residue pairs, respectively, affecting the heme-Fe atom coordination state. In conclusion, the modulation of monomeric globins reactivity by non-covalent and covalent modifications appears a very widespread phenomenon, opening new perspectives in cell survival and protection. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. |
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| Keywords: | Cygb, cytoglobin CYGB, human cytoglobin Hb, hemoglobin hhMb, horse heart myoglobin Mb, myoglobin Ngb, neuroglobin NGB, human neuroglobin swMb, sperm whale Mb |
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