View source for Cytochrome c oxidase subunit III

{{short description|Enzyme of the respiratory chain encoded by the mitochondrial genome}}
{{Redirect|COX3|the cyclooxygenase isoenzyme|COX-3}}
{{Infobox_gene}}
[[File:Map of the human mitochondrial genome.svg|thumb|320px|Location of the ''MT-CO3'' gene in the human mitochondrial genome. ''MT-CO3'' is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).]]
{{Pfam_box
| Symbol = COX3
| Name = Cytochrome c oxidase subunit III
| image = PDB_1occ_EBI.jpg
| width =
| caption = Structure of the 13-subunit oxidized cytochrome c oxidase.<ref name="pmid15299438">{{cite journal | vauthors = Miki K, Sogabe S, Uno A, Ezoe T, Kasai N, Saeda M, Matsuura Y, Miki M | title = Application of an automatic molecular-replacement procedure to crystal structure analysis of cytochrome c2 from Rhodopseudomonas viridis | journal = Acta Crystallographica Section D | volume = 50 | issue = Pt 3 | pages = 271–5 | date = May 1994 | pmid = 15299438 | doi = 10.1107/S0907444993013952 | bibcode = 1994AcCrD..50..271M | doi-access = free }}</ref>
| Pfam= PF00510
| InterPro= IPR000298
| SMART=
| PROSITE = PDOC50253
| SCOP = 1occ
| TCDB =  3.D.4
| OPM family= 4
| OPM protein= 1v55
| CDD= cd01665
}}

'''Cytochrome c oxidase subunit III (COX3)''' is an [[enzyme]] that in humans is encoded by the ''MT-CO3'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: COX3 cytochrome c oxidase subunit III| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4514}}{{PD-notice}}</ref> It is one of main [[Transmembrane protein|transmembrane]] subunits of [[cytochrome c oxidase]]. It is also one of the three [[mitochondrial DNA]] (mtDNA) encoded subunits ([[MT-CO1]], [[MT-CO2]], MT-CO3) of [[Electron transport chain#Complex IV|respiratory complex IV]]. Variants of it have been associated with isolated [[myopathy]], severe [[Encephalopathy|encephalomyopathy]], [[Leber's hereditary optic neuropathy|Leber hereditary optic neuropathy]], mitochondrial complex IV deficiency, and recurrent [[myoglobinuria]] .<ref name=":1" /><ref name=":2">{{Cite web|url=https://www.uniprot.org/uniprot/P00414|title=MT-CO3 - Cytochrome c oxidase subunit 3 - Homo sapiens (Human) - MT-CO3 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-21}}{{CC-notice|cc=by4}}</ref><ref name=":0">{{cite journal | 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 }}</ref>

== Structure ==
The ''MT-CO3'' gene produces a 30 kDa protein composed of 261 [[amino acid]]s.<ref>{{Cite web|url=https://amino.heartproteome.org/web/protein/P00414|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-08-21|archive-url=https://web.archive.org/web/20180822014906/https://amino.heartproteome.org/web/protein/P00414|archive-date=2018-08-22|url-status=dead}}</ref><ref>{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref> COX3, the protein encoded by this gene, is a member of the [[cytochrome c oxidase]] subunit 3 family. This protein is located on the [[inner mitochondrial membrane]]. COX3 is a multi-pass transmembrane protein: in human, it contains 7 [[transmembrane domain]]s at positions 15–35, 42–59, 81–101, 127–147, 159–179, 197–217, and 239–259.<ref name=":2" /><ref name=":0" />

== Function ==
[[Cytochrome c oxidase]] ({{EC number|1.9.3.1}}) is the terminal enzyme of the respiratory chain of [[mitochondria]] and many aerobic bacteria. It catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen:

: 4 cytochrome c<sup>+2</sup> + 4 H<sup>+</sup> + O<sub>2</sub> <math>\rightleftharpoons</math> 4 cytochrome c<sup>+3</sup> + 2 H<sub>2</sub>O

This reaction is coupled to the pumping of four additional protons across the mitochondrial or bacterial membrane.<ref name="PUB00006599">{{cite journal | vauthors = Michel H | title = Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping--a discussion | journal = Biochemistry | volume = 38 | issue = 46 | pages = 15129–40 | date = November 1999 | pmid = 10563795 | doi = 10.1021/bi9910934 }}</ref><ref name="PUB00033207">{{cite journal | vauthors = Belevich I, Verkhovsky MI, Wikström M | title = Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase | journal = Nature | volume = 440 | issue = 7085 | pages = 829–32 | date = April 2006 | pmid = 16598262 | doi = 10.1038/nature04619 | bibcode = 2006Natur.440..829B | s2cid = 4312050 }}</ref>

Cytochrome c oxidase is an oligomeric enzymatic complex that is located in the mitochondrial inner membrane of eukaryotes and in the plasma membrane of aerobic prokaryotes. The core structure of prokaryotic and eukaryotic cytochrome c oxidase contains three common subunits, [[Cytochrome c oxidase subunit I|I]], [[Cytochrome c oxidase subunit II|II]] and '''III'''. In prokaryotes, subunits I and III can be fused and a fourth subunit is sometimes found, whereas in eukaryotes there are a variable number of additional small subunits.<ref name="PUB00006600">{{cite journal | vauthors = Mather MW, Springer P, Hensel S, Buse G, Fee JA | title = Cytochrome oxidase genes from Thermus thermophilus. Nucleotide sequence of the fused gene and analysis of the deduced primary structures for subunits I and III of cytochrome caa3 | journal = The Journal of Biological Chemistry | volume = 268 | issue = 8 | pages = 5395–408 | date = March 1993 | doi = 10.1016/S0021-9258(18)53335-4 | pmid = 8383670 | doi-access = free }}</ref>

As the bacterial respiratory systems are branched, they have a number of distinct terminal oxidases, rather than the single cytochrome c oxidase present in the eukaryotic mitochondrial systems. Although the cytochrome o oxidases do not catalyze the cytochrome c but the quinol (ubiquinol) oxidation they belong to the same haem-copper oxidase superfamily as cytochrome c oxidases. Members of this family share sequence similarities in all three core subunits: [[Cytochrome c oxidase subunit I|subunit I]] is the most conserved subunit, whereas [[Cytochrome c oxidase subunit II|subunit II]] is the least conserved.<ref name="PUB00006601">{{cite journal | vauthors = Santana M, Kunst F, Hullo MF, Rapoport G, Danchin A, Glaser P | title = Molecular cloning, sequencing, and physiological characterization of the qox operon from Bacillus subtilis encoding the aa3-600 quinol oxidase | journal = The Journal of Biological Chemistry | volume = 267 | issue = 15 | pages = 10225–31 | date = May 1992 | doi = 10.1016/S0021-9258(19)50007-2 | pmid = 1316894 | doi-access = free }}</ref><ref name="PUB00006602">{{cite journal | vauthors = Chepuri V, Lemieux L, Au DC, Gennis RB | title = The sequence of the cyo operon indicates substantial structural similarities between the cytochrome o ubiquinol oxidase of Escherichia coli and the aa3-type family of cytochrome c oxidases | journal = The Journal of Biological Chemistry | volume = 265 | issue = 19 | pages = 11185–92 | date = July 1990 | doi = 10.1016/S0021-9258(19)38574-6 | pmid = 2162835 | doi-access = free }}</ref><ref name="PUB00002253">{{cite journal | vauthors = García-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB | title = The superfamily of heme-copper respiratory oxidases | journal = Journal of Bacteriology | volume = 176 | issue = 18 | pages = 5587–600 | date = September 1994 | pmid = 8083153 | pmc = 196760 | doi=10.1128/jb.176.18.5587-5600.1994}}</ref>

==Clinical significance==
Mutations in mtDNA-encoded cytochrome c oxidase subunit genes have been observed to be associated with isolated [[myopathy]], severe [[Encephalopathy|encephalomyopathy]], [[Leber's hereditary optic neuropathy|Leber hereditary optic neuropathy]], mitochondrial complex IV deficiency, and recurrent [[myoglobinuria]] .<ref name=":1">{{cite journal | vauthors = Horváth R, Schoser BG, Müller-Höcker J, Völpel M, Jaksch M, Lochmüller H | title = Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy | journal = Neuromuscular Disorders | volume = 15 | issue = 12 | pages = 851–7 | date = December 2005 | pmid = 16288875 | doi = 10.1016/j.nmd.2005.09.005 | s2cid = 11683931 }}</ref><ref name=":2" /><ref name=":0" />

=== Leber hereditary optic neuropathy (LHON) ===

LHON is a maternally inherited disease resulting in acute or subacute loss of central vision, due to [[optic nerve]] dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. Mutations at positions 9438 and 9804, which result in [[glycine]]-78 to [[serine]] and [[alanine]]-200 to [[threonine]] [[amino acid]] changes, have been associated with this disease.<ref>{{cite journal | vauthors = Johns DR, Neufeld MJ | title = Cytochrome c oxidase mutations in Leber hereditary optic neuropathy | journal = Biochemical and Biophysical Research Communications | volume = 196 | issue = 2 | pages = 810–5 | date = October 1993 | pmid = 8240356 | doi = 10.1006/bbrc.1993.2321 | doi-access = free }}</ref><ref name=":2" /><ref name=":0" />

=== Mitochondrial complex IV deficiency (MT-C4D) ===

Complex IV deficiency (COX deficiency) is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include [[hypertrophic cardiomyopathy]], [[hepatomegaly]] and [[Liver disease|liver dysfunction]], [[hypotonia]], [[muscle weakness]], [[exercise intolerance]], [[Specific developmental disorder|developmental delay]], [[Developmental coordination disorder|delayed motor development]], [[Intellectual disability|mental retardation]], [[Lactic acidosis|lactic acidemia]], [[encephalopathy]], [[ataxia]], and [[Heart arrhythmia|cardiac arrhythmia]]. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death and a subset of patients manifest [[Leigh syndrome]]. The mutations G7970T and G9952A have been associated with this disease.''<ref name=":1" />''<ref>{{cite journal | vauthors = Hanna MG, Nelson IP, Rahman S, Lane RJ, Land J, Heales S, Cooper MJ, Schapira AH, Morgan-Hughes JA, Wood NW | title = Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA | journal = American Journal of Human Genetics | volume = 63 | issue = 1 | pages = 29–36 | date = July 1998 | pmid = 9634511 | pmc = 1377234 | doi = 10.1086/301910 }}</ref><ref name=":2" /><ref name=":0" />

=== Recurrent myoglobinuria mitochondrial (RM-MT) ===

Recurrent myoglobinuria is characterized by recurrent attacks of [[rhabdomyolysis]] ([[necrosis]] or disintegration of skeletal muscle) associated with muscle pain and weakness, and followed by excretion of [[myoglobin]] in the urine. It has been associated with mitochondrial complex IV deficiency.<ref>{{cite journal | vauthors = Keightley JA, Hoffbuhr KC, Burton MD, Salas VM, Johnston WS, Penn AM, Buist NR, Kennaway NG | title = A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria | journal = Nature Genetics | volume = 12 | issue = 4 | pages = 410–6 | date = April 1996 | pmid = 8630495 | doi = 10.1038/ng0496-410 | s2cid = 13314201 }}</ref><ref name=":2" /><ref name=":0" />

== Subfamilies ==
* Cytochrome o ubiquinol oxidase, subunit III {{InterPro|IPR014206}}
* Cytochrome aa3 quinol oxidase, subunit III {{InterPro|IPR014246}}

== Interactions ==
COX3 has been shown to have 15 binary [[Protein–protein interaction|protein-protein interactions]] including 8 co-complex interactions. COX3 appears to interact with SNCA, [[KRAS]], [[RAC1]], and [[HSPB2]].<ref>{{Cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=COX3 | title = 2 binary interactions found for search term COX3 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-21 }}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA | title = Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region | journal = Molecular and Cellular Biology | volume = 11 | issue = 3 | pages = 1631–7 | date = March 1991 | pmid = 1996112 | pmc = 369459 | doi =  10.1128/MCB.11.3.1631}}
* {{cite journal | vauthors = Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G | title = URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit | journal = Science | volume = 234 | issue = 4776 | pages = 614–8 | date = October 1986 | pmid = 3764430 | doi = 10.1126/science.3764430 | bibcode = 1986Sci...234..614C }}
* {{cite journal | vauthors = Chomyn A, Mariottini P, Cleeter MW, Ragan CI, Matsuno-Yagi A, Hatefi Y, Doolittle RF, Attardi G | title = Six unidentified reading frames of human mitochondrial DNA encode components of the respiratory-chain NADH dehydrogenase | journal = Nature | volume = 314 | issue = 6012 | pages = 592–7 | year = 1985 | pmid = 3921850 | doi = 10.1038/314592a0 | bibcode = 1985Natur.314..592C | s2cid = 32964006 }}
* {{cite journal | vauthors = 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 | title = Sequence and organization of the human mitochondrial genome | journal = Nature | volume = 290 | issue = 5806 | pages = 457–65 | date = April 1981 | pmid = 7219534 | doi = 10.1038/290457a0 | bibcode = 1981Natur.290..457A | s2cid = 4355527 }}
* {{cite journal | vauthors = Montoya J, Ojala D, Attardi G | title = Distinctive features of the 5'-terminal sequences of the human mitochondrial mRNAs | journal = Nature | volume = 290 | issue = 5806 | pages = 465–70 | date = April 1981 | pmid = 7219535 | doi = 10.1038/290465a0 | bibcode = 1981Natur.290..465M | s2cid = 4358928 }}
* {{cite journal | vauthors = Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N | title = Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA | journal = Nature Genetics | volume = 23 | issue = 2 | pages = 147 | date = October 1999 | pmid = 10508508 | doi = 10.1038/13779 | s2cid = 32212178 | doi-access = free }}
* {{cite journal | vauthors = Ingman M, Kaessmann H, Pääbo S, Gyllensten U | title = Mitochondrial genome variation and the origin of modern humans | journal = Nature | volume = 408 | issue = 6813 | pages = 708–13 | date = December 2000 | pmid = 11130070 | doi = 10.1038/35047064 | bibcode = 2000Natur.408..708I | s2cid = 52850476 }}
* {{cite journal | vauthors = Maca-Meyer N, González AM, Larruga JM, Flores C, Cabrera VM | title = Major genomic mitochondrial lineages delineate early human expansions | journal = BMC Genetics | volume = 2 | pages = 13 | year = 2003 | issue = 1 | pmid = 11553319 | pmc = 55343 | doi = 10.1186/1471-2156-2-13 | doi-access = free }}
* {{cite journal | vauthors = Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N | title = Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups | journal = American Journal of Human Genetics | volume = 70 | issue = 5 | pages = 1152–71 | date = May 2002 | pmid = 11938495 | pmc = 447592 | doi = 10.1086/339933 }}
* {{cite journal | vauthors = Silva WA, Bonatto SL, Holanda AJ, Ribeiro-Dos-Santos AK, Paixão BM, Goldman GH, Abe-Sandes K, Rodriguez-Delfin L, Barbosa M, Paçó-Larson ML, Petzl-Erler ML, Valente V, Santos SE, Zago MA | title = Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America | journal = American Journal of Human Genetics | volume = 71 | issue = 1 | pages = 187–92 | date = July 2002 | pmid = 12022039 | pmc = 384978 | doi = 10.1086/341358 }}
* {{cite journal | vauthors = Elkon H, Don J, Melamed E, Ziv I, Shirvan A, Offen D | title = Mutant and wild-type alpha-synuclein interact with mitochondrial cytochrome C oxidase | journal = Journal of Molecular Neuroscience | volume = 18 | issue = 3 | pages = 229–38 | date = June 2002 | pmid = 12059041 | doi = 10.1385/JMN:18:3:229 | s2cid = 42265181 }}
* {{cite journal | vauthors = Mishmar D, Ruiz-Pesini E, Golik P, Macaulay V, Clark AG, Hosseini S, Brandon M, Easley K, Chen E, Brown MD, Sukernik RI, Olckers A, Wallace DC | title = Natural selection shaped regional mtDNA variation in humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 1 | pages = 171–6 | date = January 2003 | pmid = 12509511 | pmc = 140917 | doi = 10.1073/pnas.0136972100 | bibcode = 2003PNAS..100..171M | doi-access = free }}
* {{cite journal | vauthors = Ingman M, Gyllensten U | title = Mitochondrial genome variation and evolutionary history of Australian and New Guinean aborigines | journal = Genome Research | volume = 13 | issue = 7 | pages = 1600–6 | date = July 2003 | pmid = 12840039 | pmc = 403733 | doi = 10.1101/gr.686603 }}
* {{cite journal | vauthors = Kong QP, Yao YG, Sun C, Bandelt HJ, Zhu CL, Zhang YP | title = Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences | journal = American Journal of Human Genetics | volume = 73 | issue = 3 | pages = 671–6 | date = September 2003 | pmid = 12870132 | pmc = 1180693 | doi = 10.1086/377718 }}
* {{cite journal | vauthors = Temperley RJ, Seneca SH, Tonska K, Bartnik E, Bindoff LA, Lightowlers RN, Chrzanowska-Lightowlers ZM | title = Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria | journal = Human Molecular Genetics | volume = 12 | issue = 18 | pages = 2341–8 | date = September 2003 | pmid = 12915481 | doi = 10.1093/hmg/ddg238 | doi-access = free }}
* {{cite journal | vauthors = Maca-Meyer N, González AM, Pestano J, Flores C, Larruga JM, Cabrera VM | title = Mitochondrial DNA transit between West Asia and North Africa inferred from U6 phylogeography | journal = BMC Genetics | volume = 4 | pages = 15 | date = October 2003 | pmid = 14563219 | pmc = 270091 | doi = 10.1186/1471-2156-4-15 | doi-access = free }}
* {{cite journal | vauthors = Coble MD, Just RS, O'Callaghan JE, Letmanyi IH, Peterson CT, Irwin JA, Parsons TJ | title = Single nucleotide polymorphisms over the entire mtDNA genome that increase the power of forensic testing in Caucasians | journal = International Journal of Legal Medicine | volume = 118 | issue = 3 | pages = 137–46 | date = June 2004 | pmid = 14760490 | doi = 10.1007/s00414-004-0427-6 | s2cid = 8413730 }}
* {{cite journal | vauthors = Palanichamy MG, Sun C, Agrawal S, Bandelt HJ, Kong QP, Khan F, Wang CY, Chaudhuri TK, Palla V, Zhang YP | title = Phylogeny of mitochondrial DNA macrohaplogroup N in India, based on complete sequencing: implications for the peopling of South Asia | journal = American Journal of Human Genetics | volume = 75 | issue = 6 | pages = 966–78 | date = December 2004 | pmid = 15467980 | pmc = 1182158 | doi = 10.1086/425871 }}
* {{cite journal | vauthors = Starikovskaya EB, Sukernik RI, Derbeneva OA, Volodko NV, Ruiz-Pesini E, Torroni A, Brown MD, Lott MT, Hosseini SH, Huoponen K, Wallace DC | title = Mitochondrial DNA diversity in indigenous populations of the southern extent of Siberia, and the origins of Native American haplogroups | journal = Annals of Human Genetics | volume = 69 | issue = Pt 1 | pages = 67–89 | date = January 2005 | pmid = 15638829 | pmc = 3905771 | doi = 10.1046/j.1529-8817.2003.00127.x }}
* {{cite journal | vauthors = Rajkumar R, Banerjee J, Gunturi HB, Trivedi R, Kashyap VK | title = Phylogeny and antiquity of M macrohaplogroup inferred from complete mt DNA sequence of Indian specific lineages | journal = BMC Evolutionary Biology | volume = 5 | pages = 26 | date = April 2005 | pmid = 15804362 | pmc = 1079809 | doi = 10.1186/1471-2148-5-26 | doi-access = free }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1173/  GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP]

{{NLM content}}

{{Mitochondrial enzymes}}

[[Category:Protein domains]]
[[Category:Protein families]]
[[Category:Transmembrane proteins]]
[[Category:Human mitochondrial genes]]