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Kadenbach, Bernhard; Napiwotzki, Jörg; Frank, Viola; Arnold, Susanne; Exner, Stefan; Hüttemann, Maik

doi:10.1023/a:1020599209468

Cited by 26 publications

(6 citation statements)

References 52 publications

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“…On the other hand, the lack of activity in the presence of higher concentrations of cholate may be due to some additional effect. In addition, it has been suggested that ATP, which has a structure similar to cholate, can also associated with the CH2-binding site (17, 34, 35), suggesting that under physiological conditions, solutes such as ATP bind to the protein and regulate its activity.…”

Section: Resultsmentioning

confidence: 99%

Monomeric structure of an active form of bovine cytochrome c oxidase

Shinzawa‐Itoh

Sügimura

Misaki

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome c oxidase (CcO), a membrane enzyme in the respiratory chain, catalyzes oxygen reduction by coupling electron and proton transfer through the enzyme with a proton pump across the membrane. In all crystals reported to date, bovine CcO exists as a dimer with the same intermonomer contacts, whereas CcOs and related enzymes from prokaryotes exist as monomers. Recent structural analyses of the mitochondrial respiratory supercomplex revealed that CcO monomer associates with complex I and complex III, indicating that the monomeric state is functionally important. In this study, we prepared monomeric and dimeric bovine CcO, stabilized using amphipol, and showed that the monomer had high activity. In addition, using a newly synthesized detergent, we determined the oxidized and reduced structures of monomer with resolutions of 1.85 and 1.95 Å, respectively. Structural comparison of the monomer and dimer revealed that a hydrogen bond network of water molecules is formed at the entry surface of the proton transfer pathway, termed the K-pathway, in monomeric CcO, whereas this network is altered in dimeric CcO. Based on these results, we propose that the monomer is the activated form, whereas the dimer can be regarded as a physiological standby form in the mitochondrial membrane. We also determined phospholipid structures based on electron density together with the anomalous scattering effect of phosphorus atoms. Two cardiolipins are found at the interface region of the supercomplex. We discuss formation of the monomeric CcO, dimeric CcO, and supercomplex, as well as their role in regulation of CcO activity.

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Section: Resultsmentioning

confidence: 99%

Monomeric structure of an active form of bovine cytochrome c oxidase

Shinzawa‐Itoh

Sügimura

Misaki

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The original suggestion, based on crystallographic 1 and activity 20, 21, 63 studies on the mammalian oxidase, was that the cholate sites in bovC c O represented adenine nucleotide regulatory sites, due to the similar size, shape, and binding characteristics of these ligands. 1 Our current studies do not rule this out, but we did not observe significant effects of adenine nucleotides in the assay systems described here.…”

Section: Discussionmentioning

confidence: 99%

A Conserved Amphipathic Ligand Binding Region Influences K-Path-Dependent Activity of Cytochrome c Oxidase

et al. 2013

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A conserved, crystallographically-defined bile acid binding site was originally identified in the membrane domain of mammalian and bacterial cytochrome c oxidase (CcO). Current studies show other amphipathic molecules including detergents, fatty acids, steroids, and porphyrins bind to this site and affect the already 50% inhibited activity of the E101A mutant of Rhodobacter sphaeroides CcO, as well as altering the activity of wildtype and bovine enzymes. Dodecyl maltoside, Triton X100, C12E8, lysophophatidylcholine and CHOBIMALT detergents further inhibit RsCcO E101A, with lesser inhibition observed in wildtype. The detergent inhibition is overcome in the presence of μM concentrations of steroids and porphyrin analogs including deoxycholate, cholesteryl hemisuccinate, bilirubin, and protoporphyrin IX. In addition to alleviating detergent inhibition, amphipathic carboxylates including arachidonic, docosahexanoic, and phytanic acids stimulate the activity of E101A to wildtype levels by providing the missing carboxyl group. Computational modeling of dodecyl maltoside, bilirubin, and protoporphyrin IX into the conserved steroid site shows energetically favorable binding modes for these ligands and suggests that a groove at the interface of subunit I and II, including the entrance to the K-path and helix VIII of subunit I, mediates the observed competitive ligand interactions involving two overlapping sites. Spectral analysis indicates that ligand binding to this region affects CcO activity by altering the K path dependent electron transfer equilibrium between heme a and heme a3. The high affinity and specificity of a number of compounds for this region, and its conservation and impact on CcO activity, support its physiological significance.

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“…It was postulated that the decreased H + /e − ratio for the enzyme from skeletal muscle tissue (subunit VIaH) at high ATP/ADP ratios (e.g. during sleep), and for the enzyme from nonskeletal muscle tissues, participate in thermogenesis 52b, 59…”

Section: High Atp/adp Ratios Decrease the H+/e− Stoichiometry Onlymentioning

confidence: 99%

Cytochrome c Oxidase and the Regulation of Oxidative Phosphorylation

et al. 2001

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Life of higher organisms is essentially dependent on the efficient synthesis of ATP by oxidative phosphorylation in mitochondria. An important and as yet unsolved question of energy metabolism is how are the variable rates of ATP synthesis at maximal work load during exercise or mental work and at rest or during sleep regulated. This article reviews our present knowledge on the structure of bacterial and eukaryotic cytochrome c oxidases and correlates it with recent results on the regulatory functions of nuclear-coded subunits of the eukaryotic enzyme, which are absent from the bacterial enzyme. A new molecular hypothesis on the physiological regulation of oxidative phosphorylation is proposed, assuming a hormonally controlled dynamic equilibrium in vivo between two states of energy metabolism, a relaxed state with low ROS (reactive oxygen species) formation, and an excited state with elevated formation of ROS, which are known to accelerate aging and to cause degenerative diseases and cancer. The hypothesis is based on the allosteric ATP inhibition of cytochrome c oxidase at high intramitochondrial ATP/ADP ratios ("second mechanism of respiratory control"), which is switched on by cAMP-dependent phosphorylation and switched off by calcium-induced dephosphorylation of the enzyme.

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Cited by 26 publications

References 52 publications

Monomeric structure of an active form of bovine cytochrome c oxidase

Monomeric structure of an active form of bovine cytochrome c oxidase

A Conserved Amphipathic Ligand Binding Region Influences K-Path-Dependent Activity of Cytochrome c Oxidase

Cytochrome c Oxidase and the Regulation of Oxidative Phosphorylation

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