Cytochrome c oxidase protein

Boerner JL, Demory ML, Silva C et al. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol 2004 24 7059-7071. 

Buse, G., Steffens, G. J., Steffens, G. C. M., Meinecke, L., Hensel, S., and Reumkens, J., 1986, Seguence analysis of complex membrane proteins (cytochrome c oxidase), in Advanced Methods in Protein Microsequence Analysis (B. Wittman-Liebold, ed.). Springer-Verlag Berlin, pp. 3409351. 

Qin, L., Hiser, C., Mulichak, A., Garavito, R. M., Ferguson-Miller, S. (2006). Identification of conserved hpid/detergent-binding sites in a high-resolution structure of the membrane protein cytochrome c oxidase. Proceedings of the National Academy of Sciences of the United States of America, 103, 16117—16122. 

The protein cytochrome c oxidase, with a monomeric molecular weight of about 100,000, contains two a-type hemes and two copper atoms. A low-spin ferric heme signal and a so-called intrinsic copper signal near g = 2.0 are observed in the frozen solution EPR spectrum of the fully oxidized oxidase. The latter signal shows EPR features which one could assign either to a thiyl radical (R-S ) or to a cupric ion center with an unusually low g value Since no hf structure from copper is resolved at X- or Q-band frequencies, the controversy could not be solved unambiguously from EPR data alone. 

Figure 7.6 A shows SEIRAS spectra that foUow the adsorption of the protein cytochrome c oxidase onto the surface of a chemically modified Au electrode. Bands of the amide I and amide II modes of the protein backbone appear at 1658 cm" and 1550 cm", respectively. The peak intensity of the bands increases with time. The amide II band was shown to grow according to an exponential rate law with a time constant of 213 s [151]. The amide I band position is characteristic of an a-helical protein, consistent with the structure of cytochrome c oxidase. The protein was adsorbed onto the Au surface via affinity for a chemical layer that was constructed in a step-wise fashion upon exposure of the surface to a series of reagents. Initially, the metal surface was modified by self-assembly of DTSP [difhiobis-(suc-...

Many key protein ET processes have become accessible to theoretical analysis recently because of high-resolution x-ray stmctural data. These proteins include the bacterial photosynthetic reaction centre [18], nitrogenase (responsible for nitrogen fixation), and cytochrome c oxidase (the tenninal ET protein in mammals) [19, 20]. Although much is understood about ET in these molecular machines, considerable debate persists about details of the molecular transfonnations. 

Hofacker, I., Schulten, K. Oxygen and proton pathways in cytochrome-c oxidase. Proteins Str. Funct. Genet. 29 (1998) 100-107... 

Despite considerable efforts very few membrane proteins have yielded crystals that diffract x-rays to high resolution. In fact, only about a dozen such proteins are currently known, among which are porins (which are outer membrane proteins from bacteria), the enzymes cytochrome c oxidase and prostaglandin synthase, and the light-harvesting complexes and photosynthetic reaction centers involved in photosynthesis. In contrast, many other membrane proteins have yielded small crystals that diffract poorly, or not at all, using conventional x-ray sources. However, using the most advanced synchrotron sources (see Chapter 18) it is now possible to determine x-ray structures from protein crystals as small as 20 pm wide which will permit more membrane protein structures to be elucidated. 

Mammalian sulfite oxidase is the last enzyme in the pathway for degradation of sulfur-containing amino acids. Sulfite oxidase (SO) catalyzes the oxidation of sulfite (SO ) to sulfate (S04 ), using the heme-containing protein, cytochrome c, as electron acceptor ... 

Thus, Og and cytochrome c oxidase are the final destination for the electrons derived from the oxidation of food materials. In concert with this process, cytochrome c oxidase also drives transport of protons across the inner mitochondrial membrane. These important functions are carried out by a transmembrane protein complex consisting of more than 10 subunits (Table 21.2). 

Rogers MS, Dooley DM. 2001. Posttranslationally modihed tyrosines from galactose oxidase and cytochrome c oxidase. Adv Protein Chem 58 387. 

The reduction of ground state O2 with organic substances is fairly slow in aqueous or nonaqueous solutions [57] in spite of the high redox potential of O2. The O2 is utilized effectively, however, as the terminal oxidant in the respiratory chain in a biomembrane with redox enzymes composed of membrane proteins such as heme proteins containing cytochrome c oxidase [58-60] or quinol oxidase [61,62]. 

Figure 12.2 Copper chaperone function, (a) Copper homeostasis in Enterococcus hirae is affected by the proteins encoded by the cop operon. CopA, Cu1+-import ATPase CopB, Cu1+-export ATPase CopY, Cu1+-responsive repressor copZ, chaperone for Cu1+ delivery to CopY. (b) The CTR family of proteins transports copper into yeast cells. Atxlp delivers copper to the CPx-type ATPases located in the post Golgi apparatus for the maturation of Fet3p. (c) Coxl7p delivers copper to the mitochondrial intermembrane space for incorporation into cytochrome c oxidase (CCO). (d) hCTR, a human homologue of CTR, mediates copper-ion uptake into human cells. CCS delivers copper to cytoplasmic Cu/Zn superoxide dismutase (SOD1). Abbreviations IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane PM, plasma membrane PGV, post Golgi vessel. Reprinted from Harrison et al., 2000. Copyright (2000), with permission from Elsevier Science.

Cytochrome c is responsible for accepting an electron from cytochrome Ci and transferring it to cytochrome c oxidase. The electron transfer reaction may occur via the exposed portion of the ring or by tunnelling through the protein (and involving an outer-sphere mechanism). The details of this process have not been fully elucidated and have remained the focus of much research. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

Copper is part of several essential enzymes including tyrosinase (melanin production), dopamine beta-hydroxylase (catecholamine production), copper-zinc superoxide dismutase (free radical detoxification), and cytochrome oxidase and ceruloplasmin (iron conversion) (Aaseth and Norseth 1986). All terrestrial animals contain copper as a constituent of cytochrome c oxidase, monophenol oxidase, plasma monoamine oxidase, and copper protein complexes (Schroeder et al. 1966). Excess copper causes a variety of toxic effects, including altered permeability of cellular membranes. The primary target for free cupric ions in the cellular membranes are thiol groups that reduce cupric (Cu+2) to cuprous (Cu+1) upon simultaneous oxidation to disulfides in the membrane. Cuprous ions are reoxidized to Cu+2 in the presence of molecular oxygen molecular oxygen is thereby converted to the toxic superoxide radical O2, which induces lipoperoxidation (Aaseth and Norseth 1986). 

Recent advances in measuring the kinetics of the various electron-transfer steps in this system have been achieved by use of flash photolysis of ruthenated derivatives of cytochrome c (Ru-Cc) (17-19). In these studies [Ru(bpy)3]2+ is covalently bound to a surface residue at a site that does not interfere with the docking of cytochrome c to cytochrome c oxidase. Solutions are then prepared containing both Ru-Cc and cytochrome c oxidase, and the two proteins associate to form a 1 1 complex. Flash photolysis of the solution leads directly to the excitation of the RuII(bpy)3 site, which then reduces heme c very rapidly. This method thus provides a convenient means to observe the subsequent intracomplex electron transfer from heme c to cytochrome c oxidase and further stages in the process. 

In one series of experiments the cytochrome c oxidase mutations replaced acidic residues by neutral ones, and some of them were thus expected to alter the nature of binding of the protein to cytochrome c. From the pattern of dependence of the heme c to Cua electron-transfer rate constant on these mutations it was deduced that the binding of cytochrome c to cytochrome c oxidase is mediated by electrostatic interactions between four specific acidic residues on cytochrome c oxidase and lysines on cytochrome c. In another series of experiments, tryptophan 143 of cytochrome c oxidase was mutated to Phe or Ala. These mutations had an insignificant effect on the binding of the two proteins, but they dramatically reduced the rate constant for electron transfer from heme c to Cua- It was concluded that electron transfer from... 

The realization of the widespread occurrence of amino acid radicals in enzyme catalysis is recent and has been documented in several reviews (52-61). Among the catalytically essential redox-active amino acids glycyl [e.g., anaerobic class III ribonucleotide reductase (62) and pyruvate formate lyase (63-65)], tryptophanyl [e.g., cytochrome peroxidase (66-68)], cysteinyl [class I and II ribonucleotide reductase (60)], tyrosyl [e.g., class I ribonucleotide reductase (69-71), photosystem II (72, 73), prostaglandin H synthase (74-78)], and modified tyrosyl [e.g., cytochrome c oxidase (79, 80), galactose oxidase (81), glyoxal oxidase (82)] are the most prevalent. The redox potentials of these protein residues are well within the realm of those achievable by biological oxidants. These redox enzymes have emerged as a distinct class of proteins of considerable interest and research activity. 

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