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Gene ontology
Molecular function	protein binding metal ion binding copper ion binding oxidoreductase activity cytochrome-c oxidase activity
Cellular component	respiratory chain complex IV respirasome integral component of membrane mitochondrion membrane extracellular exosome mitochondrial respiratory chain complex IV mitochondrial inner membrane
Biological process	electron transport chain response to cold lactation proton transmembrane transport mitochondrial electron transport, cytochrome c to oxygen ATP synthesis coupled electron transport positive regulation of hydrogen peroxide biosynthetic process positive regulation of necrotic cell death positive regulation of ATP biosynthetic process
Sources:Amigo /QuickGO

Orthologs

Species

Human

Mouse

Entrez


4513


17709

Ensembl


ENSG00000198712


ENSMUSG00000064354

UniProt


P00403


P00405

RefSeq (mRNA)


n/a


n/a

RefSeq (protein)


n/a


NP_904331

Location (UCSC)

Chr M: 0.01 – 0.01 Mb

PubMed search

^[3]

^[4]

Wikidata

View/Edit Human

View/Edit Mouse

Location of theMT-CO2 gene in the human mitochondrial genome.MT-CO2 is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).

Protein domain

Cytochrome c oxidase subunit II, transmembrane domain

Bacterialcytochrome c oxidase complex.Subunit II indicated by blue.

Identifiers

Symbol

COX2_TM

1occ /SCOPe /SUPFAM

Available protein structures:
Pfam	structures /ECOD
PDB	RCSB PDB;PDBe;PDBj
PDBsum	structure summary

Protein domain

Cytochrome C oxidase subunit II, periplasmic domain

Identifiers

Symbol

COX2

Available protein structures:
Pfam	structures /ECOD
PDB	RCSB PDB;PDBe;PDBj
PDBsum	structure summary

Cytochrome c oxidase II is aprotein ineukaryotes that is encoded by the MT-CO2gene.^[5] Cytochrome c oxidase subunit II, abbreviatedCOXII,COX2,COII, orMT-CO2, is the second subunit ofcytochrome c oxidase. It is also one of the threemitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2,MT-CO3) ofrespiratory complex IV.

Structure

[edit]

In humans, theMT-CO2 gene is located on thep arm ofmitochondrial DNA at position 12 and it spans 683 base pairs.^[5] TheMT-CO2 gene produces a 25.6 kDa protein composed of 227amino acids.^[6]^[7] MT-CO2 is a subunit of the enzymeCytochrome c oxidase (EC 1.9.3.1)^[8]^[9] (Complex IV), an oligomeric enzymaticcomplex of themitochondrial respiratory chain involved in the transfer ofelectrons fromcytochrome c tooxygen. In eukaryotes thisenzyme complex is located in themitochondrial inner membrane; inaerobic prokaryotes it is found in theplasma membrane. The enzyme complex consists of 3-4 subunits (prokaryotes) to up to 13polypeptides (mammals). The N-terminal domain of cytochrome C oxidase contains two transmembrane alpha-helices.^[9]^[8] The structure of MT-CO2 is known to contain one redox center and abinuclear copper A center (CuA). TheCuA is located in a conservedcysteine loop at 196 and 200amino acid positions and conservedhistidine at 204. Several bacterial MT-CO2 have a C-terminal extension that contains a covalently bound haem c.^[10]^[11]

Function

[edit]

TheMT-CO2 gene encodes for the second subunit ofcytochrome c oxidase (complex IV), a component of themitochondrial respiratory chain that catalyzes thereduction ofoxygen towater. MT-CO2 is one of the three subunits which are responsible for the formation of the functional core of thecytochrome c oxidase. MT-CO2 plays an essential role in the transfer of electrons fromcytochrome c to the bimetallic center of thecatalytic subunit 1 by utilizing itsbinuclear copper A center. It contains two adjacent transmembrane regions in itsN-terminus and the major part of the protein is exposed to the periplasmic or to the mitochondrialintermembrane space, respectively. MT-CO2 provides the substrate-binding site and contains thebinuclear copper A center, probably the primary acceptor in cytochrome c oxidase.^[12]^[13]^[5]

Clinical significance

[edit]

Mitochondrial complex IV deficiency

[edit]

Variants ofMT-CO2 have been associated with themitochondrial Complex IV deficiency, a deficiency in an enzyme complex of themitochondrial respiratory chain that catalyzes the oxidation ofcytochrome c utilizingmolecular oxygen.^[14] The deficiency is characterized byheterogeneous phenotypes ranging from isolatedmyopathy to severemultisystem disease affecting several tissues and organs. Other Clinical Manifestations includehypertrophic cardiomyopathy,hepatomegaly andliver dysfunction,hypotonia,muscle weakness,exercise intolerance,developmental disability, delayedmotor development andmental retardation.^[15] Mutations ofMT-CO2 is also known to causeLeigh's disease, which may be caused by an abnormality or deficiency ofcytochrome oxidase.^[9]^[8]

A wide range of symptoms have been found in patients with pathogenic mutations in theMT-CO2 gene with themitochondrial Complex IV deficiency. Adeletion mutation of a single nucleotide (7630delT) in the gene has been found to cause symptoms of reversibleaphasia, righthemiparesis,hemianopsia,exercise intolerance, progressivemental impairment, and shortstature.^[16] Furthermore, a patient with anonsense mutation (7896G>A) of the gene resulted in phenotypes such asshort stature, lowweight,microcephaly,skin abnormalities, severehypotonia, and normalreflexes.^[17] A novelheteroplasmic mutation (7587T>C) which altered the initiation codon of theMT-CO2 gene in patients have shown clinical manifestations such as progressive gaitataxia,cognitive impairment, bilateraloptic atrophy,pigmentary retinopathy, a decrease incolor vision, and mild distal-muscle wasting.^[18]

Others

[edit]

Juvenilemyopathy,encephalopathy,lactic acidosis, andstroke have also been associated with mutations in theMT-CO2 gene.^[5]

Interactions

[edit]

MT-CO2 is known to interact withcytochrome c by the utilization of a lysine ring around thecarboxyl containingheme edge ofcytochrome c in MT-CO2, including glutamate 129, aspartate 132, and glutamate 19.

References

[edit]

^^a ^b ^cGRCh38: Ensembl release 89: ENSG00000198712 –Ensembl, May 2017
^^a ^b ^cGRCm38: Ensembl release 89: ENSMUSG00000064354 –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 ^d"Entrez Gene: COX2 cytochrome c oxidase subunit II". This article incorporates text from this source, which is in thepublic domain.
^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 (October 2013)."Integration of cardiac proteome biology and medicine by a specialized knowledgebase".Circulation Research.113 (9):1043–53.doi:10.1161/CIRCRESAHA.113.301151.PMC 4076475.PMID 23965338.
^"Cytochrome c oxidase subunit 2".Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).^{[permanent dead link]}
^^a ^b ^cCapaldi RA, Malatesta F, Darley-Usmar VM (July 1983). "Structure of cytochrome c oxidase".Biochimica et Biophysica Acta (BBA) - Reviews on Bioenergetics.726 (2):135–48.doi:10.1016/0304-4173(83)90003-4.PMID 6307356.
^^a ^b ^cGarcía-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB (September 1994)."The superfamily of heme-copper respiratory oxidases".Journal of Bacteriology.176 (18):5587–600.doi:10.1128/jb.176.18.5587-5600.1994.PMC 196760.PMID 8083153.
^Capaldi RA (1990). "Structure and function of cytochrome c oxidase".Annual Review of Biochemistry.59:569–96.doi:10.1146/annurev.bi.59.070190.003033.PMID 2165384.
^Hill BC (April 1993). "The sequence of electron carriers in the reaction of cytochrome c oxidase with oxygen".Journal of Bioenergetics and Biomembranes.25 (2):115–20.doi:10.1007/bf00762853.PMID 8389744.S2CID 45975377.
^"MT-CO2 - Cytochrome c oxidase subunit 2 - Homo sapiens (Human) - MT-CO2 gene & protein". Retrieved2018-08-07. This article incorporatestext available under theCC 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.
^Ostergaard E, Weraarpachai W, Ravn K, Born AP, Jønson L, Duno M, Wibrand F, Shoubridge EA, Vissing J (March 2015). "Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature".Journal of Medical Genetics.52 (3):203–7.doi:10.1136/jmedgenet-2014-102914.PMID 25604084.S2CID 43018915.
^"Mitochondrial complex IV deficiency".www.uniprot.org.
^Rossmanith W, Freilinger M, Roka J, Raffelsberger T, Moser-Thier K, Prayer D, Bernert G, Bittner RE (February 2008)."Isolated cytochrome c oxidase deficiency as a cause of MELAS".Journal of Medical Genetics.45 (2):117–21.doi:10.1136/jmg.2007.052076.PMC 3027970.PMID 18245391.
^Campos Y, García-Redondo A, Fernández-Moreno MA, Martínez-Pardo M, Goda G, Rubio JC, Martín MA, del Hoyo P, Cabello A, Bornstein B, Garesse R, Arenas J (September 2001). "Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene".Annals of Neurology.50 (3):409–13.doi:10.1002/ana.1141.PMID 11558799.S2CID 23891106.
^Clark KM, Taylor RW, Johnson MA, Chinnery PF, Chrzanowska-Lightowlers ZM, Andrews RM, Nelson IP, Wood NW, Lamont PJ, Hanna MG, Lightowlers RN, Turnbull DM (May 1999)."An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy".American Journal of Human Genetics.64 (5):1330–9.doi:10.1086/302361.PMC 1377869.PMID 10205264.

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Moraes CT, Andreetta F, Bonilla E, Shanske S, DiMauro S, Schon EA (March 1991)."Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region".Molecular and Cellular Biology.11 (3):1631–7.doi:10.1128/MCB.11.3.1631.PMC 369459.PMID 1996112.
Power MD, Kiefer MC, Barr PJ, Reeves R (August 1989)."Nucleotide sequence of human mitochondrial cytochrome c oxidase II cDNA".Nucleic Acids Research.17 (16): 6734.doi:10.1093/nar/17.16.6734.PMC 318375.PMID 2550900.
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Mitochondrial proteins

Outer membrane

fatty acid degradation	Carnitine palmitoyltransferase I Long-chain-fatty-acid—CoA ligase
tryptophan metabolism	Kynureninase
monoamine neurotransmitter metabolism	Monoamine oxidase

Intermembrane space

Inner membrane

oxidative phosphorylation	Coenzyme Q – cytochrome c reductase Cytochrome c NADH dehydrogenase Succinate dehydrogenase
pyrimidine metabolism	Dihydroorotate dehydrogenase
mitochondrial shuttle	Malate-aspartate shuttle Glycerol phosphate shuttle
steroidogenesis	Cholesterol side-chain cleavage enzyme Steroid 11-beta-hydroxylase Aldosterone synthase
other	Glutamate aspartate transporter Glycerol-3-phosphate dehydrogenase ATP synthase Carnitine palmitoyltransferase II Uncoupling protein

Matrix

citric acid cycle	Citrate synthase Aconitase Isocitrate dehydrogenase Oxoglutarate dehydrogenase complex Succinyl coenzyme A synthetase Fumarase Malate dehydrogenase
anaplerotic reactions	Aspartate transaminase Glutamate dehydrogenase Pyruvate dehydrogenase complex
urea cycle	Carbamoyl phosphate synthetase I Ornithine transcarbamylase N-Acetylglutamate synthase
alcohol metabolism	ALDH2
PMPCB

Other/to be sorted

Mitochondrial DNA

Complex I	MT-ND1 MT-ND2 MT-ND3 MT-ND4 MT-ND4L MT-ND5 MT-ND6
Complex III	MT-CYB
Complex IV	MT-CO1 MT-CO2 MT-CO3
ATP synthase	MT-ATP6 MT-ATP8
tRNA	MT-TA MT-TC MT-TD MT-TE MT-TF MT-TG MT-TH MT-TI MT-TK MT-TL1 MT-TL2 MT-TM MT-TN MT-TP MT-TQ MT-TR MT-TS1 MT-TS2 MT-TT MT-TV MT-TW MT-TY