Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1)
The protein contains 169 amino acids for an estimated molecular weight of 19577 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 subunbit 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:
- 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.
- 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 |
|---|---|
| dbSNP:rs11557187 | |
| empty | |
| MC4DN16 |
Biological Process
Generation of precursor metabolites and energy
Mitochondrial electron transport, cytochrome c to oxygen
Response to nutrient
The reference OMIM entry for this protein is 123864
Cytochrome c oxidase, subunit iv, isoform 1; cox4i1
Cytochrome c oxidase, subunit iv; cox4
DESCRIPTION
COX subunit IV is the largest nucleus-encoded subunit of cytochrome c oxidase (COX; EC 1.9.3.1), the terminal enzyme complex of the mitochondrial electron transport chain. COX is an example of an unusual class of multisubunit enzyme complex found in both mitochondria and chloroplasts of eukaryotic cells. The novel feature of these complexes is their mixed genetic origin: in each complex, at least one of the polypeptide subunits is encoded in the genome of the organelle, with the remaining subunits encoded in the nucleus. Thus, 2 distinct genetic systems, each with its unique features and evolutionary constraints, must interact to produce these essential holoenzymes (summary by Lomax et al., 1992). See 220110 for a discussion of COX deficiency.CLONING
Zeviani et al. (1987) isolated a human liver cDNA encoding COX4. Bachman et al. (1999) isolated the COX4 gene. Northern blot analysis detected a 0.7-kb COX4 transcript in all adult human tissues tested, namely liver, pancreas, heart, lung, kidney, brain, skeletal muscle, and placenta. COX4 expression levels were highest in pancreas and moderate in heart, skeletal muscle, and placenta. The expression levels of COX4 and NOC4 varied concordantly in different tissues.GENE STRUCTURE
Bachman et al. (1999) determined that the COX4 gene spans approximately 7.4 kb and contains 5 exons. During analysis of the promoter region of COX4, Bachman et al. (1999) identified the novel gene 'neighbor of COX4' (NOC4; 604886). The NOC4 gene is located 5-prime to the COX4 gene in a head-to-head orientation. The transcription start sites of the 2 genes are within 250 bp of each other. The bidirectional promoter is GC-rich, lacks TATA and CCAAT elements, and contains multiple potential binding sites for SP1 (189906) and NRF2 (600492).MAPPING
Darras et al. (1987) and Lomax et al. (1990) mapped the gene for subunit IV of cytochrome c oxidase (COX) to chromosome 16q22-qter by study of Chinese hamster/human somatic cell hybrids. A pseudogene, COX4P1, was located on 14q21-qter. Makris et al. (1996) mapped the Cox4 gene to mouse chromosome 8 by haplotype analysis of progeny from an interspecific backcross.EVOLUTION
The mitochondrial genome in primates appears to accumulate mutations at a rate higher than that of single-copy nuclear DNA (Brown et al., 1982), although the evolution consists primarily of silent changes. The rates of sequence evolution have changed in different phylogenetic groups and have decreased in the primate lineage leading to humans. The changes in rate affect both substitutions leading to amino acid replacements and silent, presumably neutral, changes, although the mechanism(s) leading to the decreased rate in higher primates is unknown. Lomax et al. (1992) analyzed the expressed COX4 gene in human, bovine, rat, and mouse and the COX4 pseudogene in human, chimpanzee, orangutan, squirrel monkey, and bovine; from a comparison of the sequences, they constructed the sequence of the ancestral mammalian COX4 gene. They deduced that the human gene had evolved rapidly since the origin of the primate pseudogene approximately 41 million years ago and proposed that this resulted from coevolution of nuclear and mitochondrial genes for cytochrome c oxidase. ... More on the omim web site
June 30, 2020: Protein entry updated
Automatic update: OMIM entry 123864 was added.
March 3, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).