Multiple phosphorylations of cytochrome c oxidase and their functions |
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Authors: | Helling Stefan Hüttemann Maik Ramzan Rabia Kim Su Hyeon Lee Icksoo Müller Thorsten Langenfeld Elmar Meyer Helmut E Kadenbach Bernhard Vogt Sebastian Marcus Katrin |
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Affiliation: | 1. Kardiovaskul?res Forschungslabor, Biomedizinisches Forschungszentrum der Philipps, Universit?t Marburg, , Marburg, Germany;2. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, , Detroit, MI, USA;3. Medizinisches Proteom‐Center, Funktionelle Proteomik, Ruhr‐Universit?t Bochum, , Bochum, Germany;4. Medical Proteomics/Bioanalytics, Medizinisches Proteom-Center, Ruhr‐Universit?t Bochum, , Bochum, Germany;5. Fachbereich Chemie, Philipps‐Universit?t, , Marburg, Germany |
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Abstract: | Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial electron transport chain, is regulated by isozyme expression, allosteric effectors such as the ATP/ADP ratio, and reversible phosphorylation. Of particular interest is the "allosteric ATP-inhibition," which has been hypothesized to keep the mitochondrial membrane potential at low healthy values (<140 mV), thus preventing the formation of superoxide radical anions, which have been implicated in multiple degenerative diseases. It has been proposed that the "allosteric ATP-inhibition" is switched on by the protein kinase A-dependent phosphorylation of COX. The goal of this study was to identify the phosphorylation site(s) involved in the "allosteric ATP-inhibition" of COX. We report the mass spectrometric identification of four new phosphorylation sites in bovine heart COX. The identified phosphorylation sites include Tyr-218 in subunit II, Ser-1 in subunit Va, Ser-2 in subunit Vb, and Ser-1 in subunit VIIc. With the exception of Ser-2 in subunit Vb, the identified phosphorylation sites were found in enzyme samples with and without "allosteric ATP inhibition," making Ser-2 of subunit Vb a candidate site enabling allosteric regulation. We therefore hypothesize that additional phosphorylation(s) may be required for the "allosteric ATP-inhibition," and that these sites may be easily dephosphorylated or difficult to identify by mass spectrometry. |
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Keywords: | Allosteric ATP‐inhibition Cell biology Cytochrome c oxidase Enzyme kinetics Mass spectrometry Protein phosphorylation |
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