CX6A2_HUMAN
ID CX6A2_HUMAN Reviewed; 97 AA.
AC Q02221; O00761; Q6GTW6;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Cytochrome c oxidase subunit 6A2, mitochondrial;
DE AltName: Full=Cytochrome c oxidase polypeptide VIa-heart;
DE Short=COXVIAH;
DE AltName: Full=Cytochrome c oxidase subunit VIA-muscle;
DE Short=COX VIa-M;
DE Flags: Precursor;
GN Name=COX6A2; Synonyms=COX6A, COX6AH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=1327966; DOI=10.1016/0378-1119(92)90288-z;
RA Fabrizi G.M., Sadlock J., Hirano M., Mita S., Koga Y., Rizzuto R.,
RA Zeviani M., Schon E.A.;
RT "Differential expression of genes specifying two isoforms of subunit VIa of
RT human cytochrome c oxidase.";
RL Gene 119:307-312(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9177785; DOI=10.1006/geno.1997.4687;
RA Bachman N.J., Riggs P.K., Siddiqui N.Y., Makris G.J., Womack J.E.,
RA Lomax M.I.;
RT "Structure of the human gene (COX6A2) for the heart/muscle isoform of
RT cytochrome c oxidase subunit VIa and its chromosomal location in humans,
RT mice, and cattle.";
RL Genomics 42:146-151(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP TISSUE SPECIFICITY, FUNCTION, INVOLVEMENT IN MC4DN18, VARIANTS MC4DN18
RP ARG-39 AND ARG-43, AND CHARACTERIZATION OF VARIANTS MC4DN18 ARG-39 AND
RP ARG-43.
RX PubMed=31155743; DOI=10.1002/ana.25517;
RA Inoue M., Uchino S., Iida A., Noguchi S., Hayashi S., Takahashi T.,
RA Fujii K., Komaki H., Takeshita E., Nonaka I., Okada Y., Yoshizawa T.,
RA Van Lommel L., Schuit F., Goto Y.I., Mimaki M., Nishino I.;
RT "COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.";
RL Ann. Neurol. 86:193-202(2019).
CC -!- FUNCTION: Component of the cytochrome c oxidase, the last enzyme in the
CC mitochondrial electron transport chain which drives oxidative
CC phosphorylation. The respiratory chain contains 3 multisubunit
CC complexes succinate dehydrogenase (complex II, CII), ubiquinol-
CC cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III,
CC CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to
CC transfer electrons derived from NADH and succinate to molecular oxygen,
CC creating an electrochemical gradient over the inner membrane that
CC drives transmembrane transport and the ATP synthase. Cytochrome c
CC oxidase is the component of the respiratory chain that catalyzes the
CC reduction of oxygen to water. Electrons originating from reduced
CC cytochrome c in the intermembrane space (IMS) are transferred via the
CC dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1
CC to the active site in subunit 1, a binuclear center (BNC) formed by
CC heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2
CC water molecules unsing 4 electrons from cytochrome c in the IMS and 4
CC protons from the mitochondrial matrix. Plays a role in the assembly and
CC stabilization of complex IV (PubMed:31155743).
CC {ECO:0000250|UniProtKB:P32799, ECO:0000269|PubMed:31155743}.
CC -!- PATHWAY: Energy metabolism; oxidative phosphorylation.
CC {ECO:0000250|UniProtKB:P32799}.
CC -!- SUBUNIT: Component of the cytochrome c oxidase (complex IV, CIV), a
CC multisubunit enzyme composed of 14 subunits. The complex is composed of
CC a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in
CC the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or
CC COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C,
CC COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded
CC in the nuclear genome (By similarity). The complex exists as a monomer
CC or a dimer and forms supercomplexes (SCs) in the inner mitochondrial
CC membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and
CC ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex
CC III, CIII), resulting in different assemblies (supercomplex
CC SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (By similarity).
CC {ECO:0000250|UniProtKB:P07471}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:P07471}; Single-pass membrane protein
CC {ECO:0000250|UniProtKB:P07471}.
CC -!- TISSUE SPECIFICITY: Expressed specifically in heart and muscle
CC (PubMed:31155743). Not detected in brain, colon, spleen, kidney, liver,
CC lung and pancreas (PubMed:31155743). {ECO:0000269|PubMed:1327966,
CC ECO:0000269|PubMed:31155743}.
CC -!- DISEASE: Mitochondrial complex IV deficiency, nuclear type 18 (MC4DN18)
CC [MIM:619062]: An autosomal recessive, muscle-specific, mitochondrial
CC disorder with onset in infancy. MC4DN18 is characterized by hypotonia,
CC limb and facial muscle weakness, and high arched palate. Some patients
CC have respiratory insufficiency at birth and cardiomyopathy. Patient
CC skeletal muscle shows decreased levels and activity of mitochondrial
CC respiratory complex IV. {ECO:0000269|PubMed:31155743}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome c oxidase subunit 6A family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M83308; AAA52062.1; -; mRNA.
DR EMBL; U66875; AAC51328.1; -; Genomic_DNA.
DR EMBL; BC029818; AAH29818.1; -; mRNA.
DR CCDS; CCDS10712.1; -.
DR PIR; JC1304; OGHU6A.
DR RefSeq; NP_005196.1; NM_005205.3.
DR AlphaFoldDB; Q02221; -.
DR SMR; Q02221; -.
DR BioGRID; 107732; 5.
DR IntAct; Q02221; 10.
DR STRING; 9606.ENSP00000287490; -.
DR DrugBank; DB02659; Cholic Acid.
DR DrugBank; DB04464; N-Formylmethionine.
DR TCDB; 3.D.4.11.1; the proton-translocating cytochrome oxidase (cox) superfamily.
DR PhosphoSitePlus; Q02221; -.
DR BioMuta; COX6A2; -.
DR DMDM; 116241323; -.
DR MassIVE; Q02221; -.
DR PaxDb; Q02221; -.
DR PeptideAtlas; Q02221; -.
DR PRIDE; Q02221; -.
DR ProteomicsDB; 58061; -.
DR Antibodypedia; 27872; 106 antibodies from 29 providers.
DR DNASU; 1339; -.
DR Ensembl; ENST00000287490.5; ENSP00000287490.4; ENSG00000156885.6.
DR GeneID; 1339; -.
DR KEGG; hsa:1339; -.
DR MANE-Select; ENST00000287490.5; ENSP00000287490.4; NM_005205.4; NP_005196.1.
DR UCSC; uc002ebx.2; human.
DR CTD; 1339; -.
DR DisGeNET; 1339; -.
DR GeneCards; COX6A2; -.
DR HGNC; HGNC:2279; COX6A2.
DR HPA; ENSG00000156885; Group enriched (heart muscle, skeletal muscle, tongue).
DR MalaCards; COX6A2; -.
DR MIM; 602009; gene.
DR MIM; 619062; phenotype.
DR neXtProt; NX_Q02221; -.
DR OpenTargets; ENSG00000156885; -.
DR Orphanet; 254905; Isolated cytochrome C oxidase deficiency.
DR PharmGKB; PA26796; -.
DR VEuPathDB; HostDB:ENSG00000156885; -.
DR eggNOG; KOG3469; Eukaryota.
DR GeneTree; ENSGT00940000162257; -.
DR HOGENOM; CLU_122515_1_1_1; -.
DR InParanoid; Q02221; -.
DR OMA; IRTKPYC; -.
DR OrthoDB; 1591077at2759; -.
DR PhylomeDB; Q02221; -.
DR TreeFam; TF105064; -.
DR PathwayCommons; Q02221; -.
DR SignaLink; Q02221; -.
DR UniPathway; UPA00705; -.
DR BioGRID-ORCS; 1339; 12 hits in 1068 CRISPR screens.
DR ChiTaRS; COX6A2; human.
DR GenomeRNAi; 1339; -.
DR Pharos; Q02221; Tbio.
DR PRO; PR:Q02221; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q02221; protein.
DR Bgee; ENSG00000156885; Expressed in hindlimb stylopod muscle and 117 other tissues.
DR Genevisible; Q02221; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005751; C:mitochondrial respiratory chain complex IV; IBA:GO_Central.
DR GO; GO:0004129; F:cytochrome-c oxidase activity; IEA:InterPro.
DR GO; GO:0030234; F:enzyme regulator activity; IBA:GO_Central.
DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc.
DR GO; GO:0006123; P:mitochondrial electron transport, cytochrome c to oxygen; IBA:GO_Central.
DR CDD; cd00925; Cyt_c_Oxidase_VIa; 1.
DR Gene3D; 4.10.95.10; -; 1.
DR InterPro; IPR001349; Cyt_c_oxidase_su6a.
DR InterPro; IPR018507; Cyt_c_oxidase_su6a_CS.
DR InterPro; IPR036418; Cyt_c_oxidase_su6a_sf.
DR PANTHER; PTHR11504; PTHR11504; 1.
DR Pfam; PF02046; COX6A; 1.
DR PIRSF; PIRSF000277; COX6A1; 1.
DR SUPFAM; SSF81411; SSF81411; 1.
DR PROSITE; PS01329; COX6A; 1.
PE 1: Evidence at protein level;
KW Disease variant; Membrane; Mitochondrion; Mitochondrion inner membrane;
KW Oxidoreductase; Primary mitochondrial disease; Reference proteome;
KW Transit peptide; Transmembrane; Transmembrane helix.
FT TRANSIT 1..12
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 13..97
FT /note="Cytochrome c oxidase subunit 6A2, mitochondrial"
FT /id="PRO_0000006116"
FT TOPO_DOM 13..24
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000250|UniProtKB:P07471"
FT TRANSMEM 25..49
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P07471"
FT TOPO_DOM 50..97
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000250|UniProtKB:P07471"
FT VARIANT 39
FT /note="S -> R (in MC4DN18; reduced complex IV assembly;
FT decreased COX6A2 protein stability; dbSNP:rs1597176845)"
FT /evidence="ECO:0000269|PubMed:31155743"
FT /id="VAR_084183"
FT VARIANT 43
FT /note="C -> R (in MC4DN18; reduced complex IV assembly;
FT decreased COX6A2 protein stability; dbSNP:rs1275864234)"
FT /evidence="ECO:0000269|PubMed:31155743"
FT /id="VAR_084184"
FT CONFLICT 55
FT /note="P -> E (in Ref. 1; AAA52062)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 97 AA; 10815 MW; 843AD80319891F1B CRC64;
MALPLRPLTR GLASAAKGGH GGAGARTWRL LTFVLALPSV ALCTFNSYLH SGHRPRPEFR
PYQHLRIRTK PYPWGDGNHT LFHNSHVNPL PTGYEHP
