Cytochrome c oxidase subunit 2 explained

Cytochrome c oxidase II is a protein in eukaryotes that is encoded by the MT-CO2 gene.^[1] Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV.

Structure

In humans, the MT-CO2 gene is located on the p arm of mitochondrial DNA at position 12 and it spans 683 base pairs. The MT-CO2 gene produces a 25.6 kDa protein composed of 227 amino acids.^{[2] [3]} MT-CO2 is a subunit of the enzyme Cytochrome c oxidase ^{[4] [5]} (Complex IV), an oligomeric enzymatic complex of the mitochondrial respiratory chain involved in the transfer of electrons from cytochrome c to oxygen. In eukaryotes this enzyme complex is located in the mitochondrial inner membrane; in aerobic prokaryotes it is found in the plasma membrane. The enzyme complex consists of 3-4 subunits (prokaryotes) to up to 13 polypeptides (mammals). The N-terminal domain of cytochrome C oxidase contains two transmembrane alpha-helices.^{[5] [4]} The structure of MT-CO2 is known to contain one redox center and a binuclear copper A center (CuA). The CuA is located in a conserved cysteine loop at 196 and 200 amino acid positions and conserved histidine at 204. Several bacterial MT-CO2 have a C-terminal extension that contains a covalently bound haem c.^{[6] [7]}

Function

The MT-CO2 gene encodes for the second subunit of cytochrome c oxidase (complex IV), a component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. MT-CO2 is one of the three subunits which are responsible for the formation of the functional core of the cytochrome c oxidase. MT-CO2 plays an essential role in the transfer of electrons from cytochrome c to the bimetallic center of the catalytic subunit 1 by utilizing its binuclear copper A center. It contains two adjacent transmembrane regions in its N-terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrial intermembrane space, respectively. MT-CO2 provides the substrate-binding site and contains the binuclear copper A center, probably the primary acceptor in cytochrome c oxidase.^{[8] [9] [1]}

Clinical significance

Mitochondrial complex IV deficiency

Variants of MT-CO2 have been associated with the mitochondrial Complex IV deficiency, a deficiency in an enzyme complex of the mitochondrial respiratory chain that catalyzes the oxidation of cytochrome c utilizing molecular oxygen.^[10] The deficiency is characterized by heterogeneous phenotypes ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Other Clinical Manifestations include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental disability, delayed motor development and mental retardation.^[11] Mutations of MT-CO2 is also known to cause Leigh's disease, which may be caused by an abnormality or deficiency of cytochrome oxidase.^{[5] [4]}

A wide range of symptoms have been found in patients with pathogenic mutations in the MT-CO2 gene with the mitochondrial Complex IV deficiency. A deletion mutation of a single nucleotide (7630delT) in the gene has been found to cause symptoms of reversible aphasia, right hemiparesis, hemianopsia, exercise intolerance, progressive mental impairment, and short stature.^[12] Furthermore, a patient with a nonsense mutation (7896G>A) of the gene resulted in phenotypes such as short stature, low weight, microcephaly, skin abnormalities, severe hypotonia, and normal reflexes.^[13] A novel heteroplasmic mutation (7587T>C) which altered the initiation codon of the MT-CO2 gene in patients have shown clinical manifestations such as progressive gait ataxia, cognitive impairment, bilateral optic atrophy, pigmentary retinopathy, a decrease in color vision, and mild distal-muscle wasting.^[14]

Others

Juvenile myopathy, encephalopathy, lactic acidosis, and stroke have also been associated with mutations in the MT-CO2 gene.

Interactions

MT-CO2 is known to interact with cytochrome c by the utilization of a lysine ring around the carboxyl containing heme edge of cytochrome c in MT-CO2, including glutamate 129, aspartate 132, and glutamate 19.

References

Further reading

• Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ . Harvesting the fruit of the human mtDNA tree . Trends in Genetics . 22 . 6 . 339–45 . June 2006 . 16678300 . 10.1016/j.tig.2006.04.001 .
• Barrell BG, Bankier AT, Drouin J . A different genetic code in human mitochondria . Nature . 282 . 5735 . 189–94 . November 1979 . 226894 . 10.1038/282189a0 . 1979Natur.282..189B . 4335828 .
• Bodenteich A, Mitchell LG, Polymeropoulos MH, Merril CR . Dinucleotide repeat in the human mitochondrial D-loop . Human Molecular Genetics . 1 . 2 . 140 . May 1992 . 1301157 . 10.1093/hmg/1.2.140-a . free .
• Lu X, Walker T, MacManus JP, Seligy VL . Differentiation of HT-29 human colonic adenocarcinoma cells correlates with increased expression of mitochondrial RNA: effects of trehalose on cell growth and maturation . Cancer Research . 52 . 13 . 3718–25 . July 1992 . 1377597 .
• Marzuki S, Noer AS, Lertrit P, Thyagarajan D, Kapsa R, Utthanaphol P, Byrne E . Normal variants of human mitochondrial DNA and translation products: the building of a reference data base . Human Genetics . 88 . 2 . 139–45 . December 1991 . 1757091 . 10.1007/bf00206061 . 28048453 .
• Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA . Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region . Molecular and Cellular Biology . 11 . 3 . 1631–7 . March 1991 . 1996112 . 369459 . 10.1128/MCB.11.3.1631.
• Power MD, Kiefer MC, Barr PJ, Reeves R . Nucleotide sequence of human mitochondrial cytochrome c oxidase II cDNA . Nucleic Acids Research . 17 . 16 . 6734 . August 1989 . 2550900 . 318375 . 10.1093/nar/17.16.6734 .
• Attardi G, Chomyn A, Doolittle RF, Mariottini P, Ragan CI . Seven unidentified reading frames of human mitochondrial DNA encode subunits of the respiratory chain NADH dehydrogenase . Cold Spring Harbor Symposia on Quantitative Biology . 51 . 1 . 103–14 . 1987 . 3472707 . 10.1101/sqb.1986.051.01.013 .
• Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G . URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit . Science . 234 . 4776 . 614–8 . October 1986 . 3764430 . 10.1126/science.3764430 . 1986Sci...234..614C .
• Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G . Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase . Nature . 314 . 6012 . 592–7 . 1985 . 3921850 . 10.1038/314592a0 . 1985Natur.314..592C . 32964006 .
• Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG . Sequence and organization of the human mitochondrial genome . Nature . 290 . 5806 . 457–65 . April 1981 . 7219534 . 10.1038/290457a0 . 1981Natur.290..457A . 4355527 .
• Montoya J, Ojala D, Attardi G . Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs . Nature . 290 . 5806 . 465–70 . April 1981 . 7219535 . 10.1038/290465a0 . 1981Natur.290..465M . 4358928 .
• Horai S, Hayasaka K, Kondo R, Tsugane K, Takahata N . Recent African origin of modern humans revealed by complete sequences of hominoid mitochondrial DNAs . Proceedings of the National Academy of Sciences of the United States of America . 92 . 2 . 532–6 . January 1995 . 7530363 . 42775 . 10.1073/pnas.92.2.532 . 1995PNAS...92..532H . free .
• Ruvolo M, Zehr S, von Dornum M, Pan D, Chang B, Lin J . Mitochondrial COII sequences and modern human origins . Molecular Biology and Evolution . 10 . 6 . 1115–35 . November 1993 . 8277847 . 10.1093/oxfordjournals.molbev.a040068 . free .
• Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B . Somatic mutations of the mitochondrial genome in human colorectal tumours . Nature Genetics . 20 . 3 . 291–3 . November 1998 . 9806551 . 10.1038/3108 . 19786796 .
• Kato MV . The mechanisms of death of an erythroleukemic cell line by p53: involvement of the microtubule and mitochondria . Leukemia & Lymphoma . 33 . 1–2 . 181–6 . March 1999 . 10194136 . 10.3109/10428199909093740 .
• Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA . Nature Genetics . 23 . 2 . 147 . October 1999 . 10508508 . 10.1038/13779 . 32212178 . free .
• Ingman M, Kaessmann H, Pääbo S, Gyllensten U . Mitochondrial genome variation and the origin of modern humans . Nature . 408 . 6813 . 708–13 . December 2000 . 11130070 . 10.1038/35047064 . 2000Natur.408..708I . 52850476 .
• Finnilä S, Lehtonen MS, Majamaa K . Phylogenetic network for European mtDNA . American Journal of Human Genetics . 68 . 6 . 1475–84 . June 2001 . 11349229 . 1226134 . 10.1086/320591 .
• Maca-Meyer N, González AM, Larruga JM, Flores C, Cabrera VM . Major genomic mitochondrial lineages delineate early human expansions . BMC Genetics . 2 . 13 . 2003 . 11553319 . 55343 . 10.1186/1471-2156-2-13 . free .

Notes and References

1. Web site: Entrez Gene: COX2 cytochrome c oxidase subunit II.
2. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
3. Web site: Cytochrome c oxidase subunit 2 . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) .
4. Capaldi RA, Malatesta F, Darley-Usmar VM . Structure of cytochrome c oxidase . Biochimica et Biophysica Acta (BBA) - Reviews on Bioenergetics . 726 . 2 . 135–48 . July 1983 . 6307356 . 10.1016/0304-4173(83)90003-4 .
5. García-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB . The superfamily of heme-copper respiratory oxidases . Journal of Bacteriology . 176 . 18 . 5587–600 . September 1994 . 8083153 . 196760 . 10.1128/jb.176.18.5587-5600.1994.
6. Capaldi RA . Structure and function of cytochrome c oxidase . Annual Review of Biochemistry . 59 . 569–96 . 1990 . 2165384 . 10.1146/annurev.bi.59.070190.003033 .
7. Hill BC . The sequence of electron carriers in the reaction of cytochrome c oxidase with oxygen . Journal of Bioenergetics and Biomembranes . 25 . 2 . 115–20 . April 1993 . 8389744 . 10.1007/bf00762853. 45975377 .
8. Web site: MT-CO2 - Cytochrome c oxidase subunit 2 - Homo sapiens (Human) - MT-CO2 gene & protein. 2018-08-07.
9. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
10. Ostergaard E, Weraarpachai W, Ravn K, Born AP, Jønson L, Duno M, Wibrand F, Shoubridge EA, Vissing J . Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature . Journal of Medical Genetics . 52 . 3 . 203–7 . March 2015 . 25604084 . 10.1136/jmedgenet-2014-102914 . 43018915 .
11. Web site: Mitochondrial complex IV deficiency . www.uniprot.org . en.
12. Rossmanith W, Freilinger M, Roka J, Raffelsberger T, Moser-Thier K, Prayer D, Bernert G, Bittner RE . Isolated cytochrome c oxidase deficiency as a cause of MELAS . Journal of Medical Genetics . 45 . 2 . 117–21 . February 2008 . 18245391 . 10.1136/jmg.2007.052076 . 3027970 .
13. Campos Y, García-Redondo A, Fernández-Moreno MA, Martínez-Pardo M, Goda G, Rubio JC, Martín MA, del Hoyo P, Cabello A, Bornstein B, Garesse R, Arenas J . Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene . Annals of Neurology . 50 . 3 . 409–13 . September 2001 . 11558799 . 10.1002/ana.1141. 23891106 .
14. Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska-Lightowlers ZM, Andrews RM, Nelson IP, Wood NW, Lamont PJ, Hanna MG, Lightowlers RN, Turnbull DM . An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy . American Journal of Human Genetics . 64 . 5 . 1330–9 . May 1999 . 10205264 . 10.1086/302361 . 1377869 .