• Stefan Helling, Maik Hüttemann, Rabia Ramzan, Su Hyeon Kim, Icksoo Lee, Thorsten Müller, Elmar Langenfeld, Helmut E Meyer, Bernhard Kadenbach, Sebastian Vogt, and Katrin Marcus.
• Medizinisches Proteom-Center, Funktionelle Proteomik, Ruhr-Universität Bochum, Bochum, Germany.
• Proteomics. 2012 Apr 1; 12 (7): 950-9.

AbstractCytochrome 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.© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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