Mechanism and energetics by which glutamic acid 242 prevents leaks in cytochrome c oxidase |
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Authors: | Ville R.I. Kaila,Michael I. Verkhovsky,Må rten Wikströ m |
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Affiliation: | a Helsinki Bioenergetics Group, Structural Biology and Biophysics Program, Institute of Biotechnology, PB 65 (Viikinkaari 1), 00014 University of Helsinki, Helsinki, Finland b Laboratory of Chemical Physics, NIDDK, National Institutes of Health, Bethesda, MD 20892-0520, USA |
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Abstract: | Cytochrome c oxidase (CcO) is the terminal enzyme of aerobic respiration. The energy released from the reduction of molecular oxygen to water is used to pump protons across the mitochondrial or bacterial membrane. The pump function introduces a mechanistic requirement of a valve that prevents protons from flowing backwards during the process. It was recently found that Glu-242, a key amino acid in transferring protons to be pumped across the membrane and to the site of oxygen reduction, fulfils the function of such a valve by preventing simultaneous contact to the pump site and to the proton-conducting D-channel (Kaila V.R.I. et al. Proc. Natl. Acad. Sci. USA 105, 2008). Here we have incorporated the valve model into the framework of the reaction mechanism. The function of the Glu valve is studied by exploring how the redox state of the surrounding metal centers, dielectric effects, and membrane potential, affects the energetics and leaks of this valve. Parallels are drawn between the dynamics of Glu-242 and the long-standing obscure difference between the metastable OH and stable O states of the binuclear center. Our model provides a suggestion for why reduction of the former state is coupled to proton translocation while reduction of the latter is not. |
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Keywords: | CcO, cytochrome c oxidase boldFont" >G&minus / boldFont" >g&minus and boldFont" >GH/ boldFont" >gH, deprotonated and protonated forms of glutamic acid 242 boldFont" >g and boldFont" >G, &ldquo down&rdquo and &ldquo up&rdquo conformational isomers of Glu-242 where the side chain points towards the D-pathway and towards the active site/proton-loading site, respectively boldFont" >X and boldFont" >XH, deprotonated and protonated forms of proton-loading site (PLS) boldFont" >B, boldFont" >B&minus , boldFont" >BH, oxidized, reduced, and reduced and protonated forms of the binuclear center (BNC) K, equilibrium constant pK, &minus log10(K) P-side, positively charged side of the membrane N-side, negatively charged side of the membrane pmf, proton motive force pT, proton transfer eT, electron transfer |
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