Cytochrome c oxidase subunit 2 (MT-CO2)
The protein contains 227 amino acids for an estimated molecular weight of 25565 Da.
Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix. (updated: Feb. 26, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is predicted to be membranous by TOPCONS.
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| Variant | Description |
|---|---|
| empty | |
| MT-C4D | |
| dbSNP:rs1569484167 | |
| empty | |
| colorectal cancer | |
| dbSNP:rs1116904 | |
| empty |
Biological Process
ATP synthesis coupled electron transport
Lactation
Mitochondrial electron transport, cytochrome c to oxygen
Positive regulation of ATP biosynthetic process
Positive regulation of hydrogen peroxide biosynthetic process
Positive regulation of necrotic cell death
Response to cold
The reference OMIM entry for this protein is 220110
Mitochondrial complex iv deficiency
Cytochrome c oxidase deficiency
Cox deficiency
A number sign (#) is used with this entry because cytochrome c oxidase deficiency can be caused by mutation in several nuclear-encoded and mitochondrial-encoded genes. Mutations associated with the disorder have been identified in several mitochondrial COX genes (MTCO1, 516030; MTCO2, 516040, MTCO3, 516050), as well as in mitochondrial tRNA(ser) (MTTS1, 590080) and tRNA(leu) (MTTL1; 590050). Mutations in nuclear genes include those in COX10 (602125), COX6B1 (124089), SCO1 (603644), FASTKD2 (612322), C12ORF62 (COX14; 614478), COX20 (614698), APOPT1 (616003), and COA3 (614775). COX deficiency caused by mutation in the SCO2 (604272), COX15 (603646), COA5 (613920), and COA6 (614772) genes has been found to be specifically associated with fatal infantile cardioencephalomyopathy (see, e.g., CEMCOX1, 604377). Cytochrome c oxidase deficiency associated with Leigh syndrome (see 256000) can be caused by mutation in the SURF1 gene (185620), COX15 gene (603646), TACO1 gene (612958), or PET100 gene (614770). Cytochrome c oxidase deficiency associated with the French Canadian type of Leigh syndrome (LSFC; 220111) is caused by mutation in the LRPPRC gene (607544).
DESCRIPTION
Complex IV (cytochrome c oxidase; EC 1.9.3.1) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). See 123995 for discussion of some of the nuclear-encoded subunits. Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare.CLINICAL FEATURES
Cytochrome c oxidase deficiency is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood (Shoubridge, 2001). Van Biervliet et al. (1977) described a Dutch family in which 3 sibs, including twin sisters, died of infantile mitochondrial myopathy, lactic acidosis, and de Toni-Fanconi-Debre renal syndrome due to cytochrome c oxidase deficiency. Lipid droplets and focal glycogen accumulation could be attributed to blockage of terminal oxidative metabolism. A similar defect in the renal tubule was presumably responsible for proteinuria, glycosuria, hyperphosphaturia, hypercalciuria, and generalized amino aciduria. Heart, liver, and brain were spared. Willems et al. (1977) reported an association between cytochrome c oxidase deficiency and Leigh encephalomyelopathy in a child who died at age 6 years. See 256000 for a full discussion of COX deficiency associated with Leigh syndrome. DiMauro et al. (1980) reported an infant with hypotonia, ptosis, diminished reflexes, poor suck, lactic acidosis, proteinuria, glucosuria, and amino aciduria who died at age 3.5 months. Muscle biopsy showed increased lipid droplets and abnormal mitochondria. Cytochrome c oxidase was decreased in skeletal muscle and kidney. Muller-Hocker et al. (1983) studied 2 Turkish sisters who developed apathy, failure of suckling, and generalized progressive muscular hypotonia in the newborn period and died at age 7 weeks. Both children had generalized hyperaminoaciduria. Hepatic encephalopathy was absent. Autopsy ... More on the omim web site
March 3, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 220110 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).