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词条 COX15
释义

  1. Structure

     Gene  Protein 

  2. Function

  3. Clinical significance

  4. Interactions

  5. References

  6. Further reading

  7. External links

{{Infobox_gene}}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.[1][2] This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis.[3] 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.[3] 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.[4][5][6]

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.[1]

Protein

The COX15 protein localizes to the inner mitochondrial membrane and has several predicted transmembrane domains.[1][7] 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.[8]

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.[4] 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.[9] COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX.[8]

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,[4] Leigh syndrome, [6] and encephalopathy.[10] 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.[11][12] A sequence variation in COX15 has also been reported to associate with determining the genetic risk for Alzheimer’s disease development.[13]

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.[14] COX15 is positively regulated by intracellular heme levels via Huntingtin-associated protein 1.[15]

References

1. ^1 2 {{cite journal | vauthors = Petruzzella V, Tiranti V, Fernandez P, Ianna P, Carrozzo R, Zeviani M | title = 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 | journal = Genomics | volume = 54 | issue = 3 | pages = 494–504 | date = December 1998 | pmid = 9878253 | pmc = | doi = 10.1006/geno.1998.5580 }}
2. ^{{cite web | title = Entrez Gene: COX15 COX15 homolog, cytochrome c oxidase assembly protein (yeast)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1355| accessdate = }}
3. ^1 {{cite journal | vauthors = Barros MH, Carlson CG, Glerum DM, Tzagoloff A | title = Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O | journal = FEBS Letters | volume = 492 | issue = 1-2 | pages = 133–8 | date = March 2001 | pmid = 11248251 | doi=10.1016/s0014-5793(01)02249-9}}
4. ^1 2 {{cite journal | vauthors = Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA | title = Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy | journal = American Journal of Human Genetics | volume = 72 | issue = 1 | pages = 101–14 | date = January 2003 | pmid = 12474143 | doi = 10.1086/345489 | pmc=378614}}
5. ^{{cite journal | vauthors = Miryounesi M, Fardaei M, Tabei SM, Ghafouri-Fard S | title = Leigh syndrome associated with a novel mutation in the COX15 gene | journal = Journal of Pediatric Endocrinology & Metabolism | volume = 29 | issue = 6 | pages = 741–4 | date = June 2016 | pmid = 26959537 | doi = 10.1515/jpem-2015-0396 }}
6. ^1 {{cite journal | vauthors = Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK | title = Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome | journal = Journal of Medical Genetics | volume = 41 | issue = 7 | pages = 540–4 | date = July 2004 | pmid = 15235026 | doi=10.1136/jmg.2003.017426 | pmc=1735852}}
7. ^{{cite journal | vauthors = Glerum DM, Muroff I, Jin C, Tzagoloff A | title = COX15 codes for a mitochondrial protein essential for the assembly of yeast cytochrome oxidase | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 19088–94 | date = July 1997 | pmid = 9228094 | doi=10.1074/jbc.272.30.19088}}
8. ^1 {{cite journal | vauthors = Swenson S, Cannon A, Harris NJ, Taylor NG, Fox JL, Khalimonchuk O | title = Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes | journal = The Journal of Biological Chemistry | volume = 291 | issue = 19 | pages = 10411–25 | date = May 2016 | pmid = 26940873 | doi = 10.1074/jbc.M115.707539 }}
9. ^{{cite journal | vauthors = Kim HJ, Khalimonchuk O, Smith PM, Winge DR | title = Structure, function, and assembly of heme centers in mitochondrial respiratory complexes | journal = Biochimica et Biophysica Acta | volume = 1823 | issue = 9 | pages = 1604–16 | date = September 2012 | pmid = 22554985 | doi = 10.1016/j.bbamcr.2012.04.008 | pmc=3601904}}
10. ^{{cite journal | vauthors = Alfadhel M, Lillquist YP, Waters PJ, Sinclair G, Struys E, McFadden D, Hendson G, Hyams L, Shoffner J, Vallance HD | title = Infantile cardioencephalopathy due to a COX15 gene defect: report and review | journal = American Journal of Medical Genetics. Part A | volume = 155A | issue = 4 | pages = 840–4 | date = April 2011 | pmid = 21412973 | doi = 10.1002/ajmg.a.33881 }}
11. ^{{Cite web|url=https://www.uniprot.org/uniprot/Q7KZN9|title=COX15 - Cytochrome c oxidase assembly protein COX15 homolog - Homo sapiens (Human) - COX15 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-22}}{{CC-notice|cc=by4}}
12. ^{{cite journal | vauthors = | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}
13. ^{{cite journal | vauthors = Vitali M, Venturelli E, Galimberti D, Benerini Gatta L, Scarpini E, Finazzi D | title = Analysis of the genes coding for subunit 10 and 15 of cytochrome c oxidase in Alzheimer's disease | journal = Journal of Neural Transmission | volume = 116 | issue = 12 | pages = 1635–41 | date = December 2009 | pmid = 19826901 | doi = 10.1007/s00702-009-0324-8 }}
14. ^{{cite journal | vauthors = Bareth B, Dennerlein S, Mick DU, Nikolov M, Urlaub H, Rehling P | title = The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation | journal = Molecular and Cellular Biology | volume = 33 | issue = 20 | pages = 4128–37 | date = October 2013 | pmid = 23979592 | doi = 10.1128/MCB.00747-13 | pmc=3811676| url = http://pubman.mpdl.mpg.de/pubman/item/escidoc:1850324/component/escidoc:1850330/1850324.pdf }}
15. ^{{cite journal | vauthors = Wang Z, Wang Y, Hegg EL | title = Regulation of the heme A biosynthetic pathway: differential regulation of heme A synthase and heme O synthase in Saccharomyces cerevisiae | journal = The Journal of Biological Chemistry | volume = 284 | issue = 2 | pages = 839–47 | date = January 2009 | pmid = 18953022 | doi = 10.1074/jbc.M804167200 | pmc=2613620}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Bugiani M, Tiranti V, Farina L, Uziel G, Zeviani M | title = Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency | journal = Journal of Medical Genetics | volume = 42 | issue = 5 | pages = e28 | date = May 2005 | pmid = 15863660 | pmc = 1736058 | doi = 10.1136/jmg.2004.029926 }}
  • {{cite journal | vauthors = Kennaway NG, Carrero-Valenzuela RD, Ewart G, Balan VK, Lightowlers R, Zhang YZ, Powell BR, Capaldi RA, Buist NR | title = Isoforms of mammalian cytochrome c oxidase: correlation with human cytochrome c oxidase deficiency | journal = Pediatric Research | volume = 28 | issue = 5 | pages = 529–35 | date = November 1990 | pmid = 2175025 | doi = 10.1203/00006450-199011000-00024 }}
  • {{cite journal | vauthors = Jaluria P, Betenbaugh M, Konstantopoulos K, Shiloach J | title = Enhancement of cell proliferation in various mammalian cell lines by gene insertion of a cyclin-dependent kinase homolog | journal = BMC Biotechnology | volume = 7 | pages = 71 | year = 2008 | pmid = 17945021 | pmc = 2164945 | doi = 10.1186/1472-6750-7-71 }}
  • {{cite journal | vauthors = Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK | title = Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome | journal = Journal of Medical Genetics | volume = 41 | issue = 7 | pages = 540–4 | date = July 2004 | pmid = 15235026 | pmc = 1735852 | doi = 10.1136/jmg.2003.017426 }}
  • {{cite journal | vauthors = Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA | title = Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy | journal = American Journal of Human Genetics | volume = 72 | issue = 1 | pages = 101–14 | date = January 2003 | pmid = 12474143 | pmc = 378614 | doi = 10.1086/345489 }}
{{refend}}

External links

  • {{UCSC gene info|COX15}}
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