Protein-coding gene in the species Homo sapiens
COX15 |
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Identifiers |
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Aliases | COX15, CEMCOX2, COX15 cytochrome c oxidase assembly homolog, cytochrome c oxidase assembly homolog, cytochrome c oxidase assembly homolog COX15 |
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External IDs | OMIM: 603646; MGI: 1920112; HomoloGene: 5848; GeneCards: COX15; OMA:COX15 - orthologs |
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Gene location (Human) |
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![Chromosome 10 (human)](//upload.wikimedia.org/wikipedia/commons/thumb/2/2f/Ideogram_human_chromosome_10.svg/300px-Ideogram_human_chromosome_10.svg.png) | Chr. | Chromosome 10 (human)[1] |
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| Band | 10q24.2 | Start | 99,711,844 bp[1] |
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End | 99,732,100 bp[1] |
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Gene location (Mouse) |
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![Chromosome 19 (mouse)](//upload.wikimedia.org/wikipedia/commons/thumb/8/82/Ideogram_house_mouse_chromosome_19.svg/260px-Ideogram_house_mouse_chromosome_19.svg.png) | Chr. | Chromosome 19 (mouse)[2] |
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| Band | 19|19 C3 | Start | 43,721,693 bp[2] |
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End | 43,741,439 bp[2] |
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RNA expression pattern |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - caput epididymis
- corpus epididymis
- tail of epididymis
- right uterine tube
- Skeletal muscle tissue of rectus abdominis
- right adrenal gland
- right adrenal cortex
- left adrenal gland
- renal medulla
- body of tongue
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| Top expressed in | - epithelium of small intestine
- external carotid artery
- internal carotid artery
- seminal vesicula
- atrium
- epithelium of stomach
- soleus muscle
- migratory enteric neural crest cell
- barrel cortex
- ciliary body
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| More reference expression data |
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BioGPS | ![](//upload.wikimedia.org/wikipedia/commons/thumb/d/d7/PBB_GE_COX15_219547_at_fs.png/250px-PBB_GE_COX15_219547_at_fs.png)
![](//upload.wikimedia.org/wikipedia/commons/thumb/0/09/PBB_GE_COX15_221550_at_fs.png/250px-PBB_GE_COX15_221550_at_fs.png) | More reference expression data |
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Gene ontology |
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Molecular function | - cytochrome-c oxidase activity
- oxidoreductase activity, acting on the CH-CH group of donors
- protein binding
- oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor
- heme binding
- molecular adaptor activity
| Cellular component | - mitochondrial respirasome
- cytochrome complex
- integral component of membrane
- mitochondrial membranes
- mitochondrion
- membrane
- nucleus
- mitochondrial inner membrane
| Biological process | - cellular respiration
- proton transmembrane transport
- respiratory chain complex IV assembly
- heme biosynthetic process
- heme A biosynthetic process
- mitochondrial electron transport, cytochrome c to oxygen
- respiratory gaseous exchange by respiratory system
| Sources:Amigo / QuickGO |
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Orthologs |
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Species | Human | Mouse |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNA) | |
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NM_004376 NM_078470 NM_001320974 NM_001320975 NM_001320976 |
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RefSeq (protein) | NP_001307903 NP_001307904 NP_001307905 NP_004367 NP_510870
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NP_001358953 NP_001358954 NP_001358955 NP_001358956 NP_001358957 |
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Location (UCSC) | Chr 10: 99.71 – 99.73 Mb | Chr 19: 43.72 – 43.74 Mb |
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PubMed search | [3] | [4] |
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Wikidata |
View/Edit Human | View/Edit Mouse |
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Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene.[5][6] This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis.[7] COX15 is also part of a three-component mono-oxygenase (ferredoxin, ferredoxin reductase, and COX15) that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule.[7] Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.[8][9][10]
Structure
Gene
The COX15 gene lies on the chromosome location of 10q24 and consists of nine exons. Two splice variants formed by alternative splicing at exon 9, COX15.1 and COX15.2, differ in the C-terminal domain of the protein and the 39-UTR of the transcript. But the functional significance of the different isoforms is still unknown.[5]
Protein
The COX15 protein localizes to the inner mitochondrial membrane and has several predicted transmembrane domains.[5][11] Four conserved histidine residues are proven to be critical for COX15 activity. Both COX15 multimerization and enzymatic activity would be impaired if the 20-residue linker region connecting the two conserved domains of COX15 is removed.[12]
Function
COX15 is one of the cytochrome c oxidase (COX) assembly factors identified in yeast, playing a key role in the biosynthetic pathway of mitochondrial heme A, the prosthetic group of cytochrome a and a3. COX15 in yeast mediates hydroxylation of the methyl group at the C-8 position of the heme O molecule to form heme A. A deletion of COX15 results in undetectable levels of heme A but detectable levels of heme O. Similar findings are observed in patients with COX15 deletion mutants, suggesting a similar functional role for COX15 in mammalian mitochondria and a similar pathogenesis for the COX deficiency.[8] In complex IV of the respiratory chain, heme A is required for the proper folding of the Cox 1 subunit and subsequent assembly. A deficiency in the formation of heme A and functional COX would lead to impaired electron transport and oxidative phosphorylation.[13] COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX.[12]
Clinical significance
COX deficiency is one of the most frequent causes of electron transport chain defects in humans. Therefore, in highly energy-demanding organs and tissues, such as brain and retinal tissue, with mutations in COX15, different clinical phenotypes are presented, such as early onset, fatal hypertrophic cardiomyopathy,[8] Leigh syndrome, [10] and encephalopathy.[14] Signs and symptoms of these diseases that can manifest include lactic acidosis, ataxia, hypotonia, seizures, respiratory distress, psychomotor retardation, vision loss, eye movement abnormalities, dysphagia, and central nervous system lesions.[15][16] A sequence variation in COX15 has also been reported to associate with determining the genetic risk for Alzheimer's disease development.[17]
Interactions
COX15 associates with Shy1 in distinct complexes, C-terminal epitope tagging of COX15 selectively affects its association to cytochrome c oxidase assembly intermediates (COA complexes). COX15 also forms complexes with maturing COX1, the heme-receiving subunit of COX, in the absence of Shy1.[18] COX15 is positively regulated by intracellular heme levels via Huntingtin-associated protein 1.[19]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000014919 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040018 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c Petruzzella V, Tiranti V, Fernandez P, Ianna P, Carrozzo R, Zeviani M (December 1998). "Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain". Genomics. 54 (3): 494–504. doi:10.1006/geno.1998.5580. PMID 9878253.
- ^ "Entrez Gene: COX15 COX15 homolog, cytochrome c oxidase assembly protein (yeast)".
- ^ a b Barros MH, Carlson CG, Glerum DM, Tzagoloff A (March 2001). "Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O". FEBS Letters. 492 (1–2): 133–8. doi:10.1016/s0014-5793(01)02249-9. PMID 11248251. S2CID 21826949.
- ^ a b c Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA (January 2003). "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy". American Journal of Human Genetics. 72 (1): 101–14. doi:10.1086/345489. PMC 378614. PMID 12474143.
- ^ Miryounesi M, Fardaei M, Tabei SM, Ghafouri-Fard S (June 2016). "Leigh syndrome associated with a novel mutation in the COX15 gene". Journal of Pediatric Endocrinology & Metabolism. 29 (6): 741–4. doi:10.1515/jpem-2015-0396. PMID 26959537. S2CID 28078188.
- ^ a b Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK (July 2004). "Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome". Journal of Medical Genetics. 41 (7): 540–4. doi:10.1136/jmg.2003.017426. PMC 1735852. PMID 15235026.
- ^ Glerum DM, Muroff I, Jin C, Tzagoloff A (July 1997). "COX15 codes for a mitochondrial protein essential for the assembly of yeast cytochrome oxidase". The Journal of Biological Chemistry. 272 (30): 19088–94. doi:10.1074/jbc.272.30.19088. PMID 9228094.
- ^ a b Swenson S, Cannon A, Harris NJ, Taylor NG, Fox JL, Khalimonchuk O (May 2016). "Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes". The Journal of Biological Chemistry. 291 (19): 10411–25. doi:10.1074/jbc.M115.707539. PMC 4858986. PMID 26940873.
- ^ Kim HJ, Khalimonchuk O, Smith PM, Winge DR (September 2012). "Structure, function, and assembly of heme centers in mitochondrial respiratory complexes". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (9): 1604–16. doi:10.1016/j.bbamcr.2012.04.008. PMC 3601904. PMID 22554985.
- ^
- ^ "COX15 - Cytochrome c oxidase assembly protein COX15 homolog - Homo sapiens (Human) - COX15 gene & protein". www.uniprot.org. Retrieved 2018-08-22.
This article incorporates text available under the CC BY 4.0 license. - ^ "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
- ^ Vitali M, Venturelli E, Galimberti D, Benerini Gatta L, Scarpini E, Finazzi D (December 2009). "Analysis of the genes coding for subunit 10 and 15 of cytochrome c oxidase in Alzheimer's disease". Journal of Neural Transmission. 116 (12): 1635–41. doi:10.1007/s00702-009-0324-8. PMID 19826901. S2CID 21914035.
- ^ Bareth B, Dennerlein S, Mick DU, Nikolov M, Urlaub H, Rehling P (October 2013). "The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation" (PDF). Molecular and Cellular Biology. 33 (20): 4128–37. doi:10.1128/MCB.00747-13. PMC 3811676. PMID 23979592.
- ^ Wang Z, Wang Y, Hegg EL (January 2009). "Regulation of the heme A biosynthetic pathway: differential regulation of heme A synthase and heme O synthase in Saccharomyces cerevisiae". The Journal of Biological Chemistry. 284 (2): 839–47. doi:10.1074/jbc.M804167200. PMC 2613620. PMID 18953022.
Further reading
- Bugiani M, Tiranti V, Farina L, Uziel G, Zeviani M (May 2005). "Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency". Journal of Medical Genetics. 42 (5): e28. doi:10.1136/jmg.2004.029926. PMC 1736058. PMID 15863660.
- Kennaway NG, Carrero-Valenzuela RD, Ewart G, Balan VK, Lightowlers R, Zhang YZ, Powell BR, Capaldi RA, Buist NR (November 1990). "Isoforms of mammalian cytochrome c oxidase: correlation with human cytochrome c oxidase deficiency". Pediatric Research. 28 (5): 529–35. doi:10.1203/00006450-199011000-00024. PMID 2175025.
- Jaluria P, Betenbaugh M, Konstantopoulos K, Shiloach J (2008). "Enhancement of cell proliferation in various mammalian cell lines by gene insertion of a cyclin-dependent kinase homolog". BMC Biotechnology. 7: 71. doi:10.1186/1472-6750-7-71. PMC 2164945. PMID 17945021.
- Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK (July 2004). "Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome". Journal of Medical Genetics. 41 (7): 540–4. doi:10.1136/jmg.2003.017426. PMC 1735852. PMID 15235026.
- Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA (January 2003). "Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy". American Journal of Human Genetics. 72 (1): 101–14. doi:10.1086/345489. PMC 378614. PMID 12474143.
External links