CX6A1_HUMAN
ID CX6A1_HUMAN Reviewed; 109 AA.
AC P12074; B2R500; O43714; Q32Q37;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1999, sequence version 4.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Cytochrome c oxidase subunit 6A1, mitochondrial;
DE AltName: Full=Cytochrome c oxidase polypeptide VIa-liver;
DE AltName: Full=Cytochrome c oxidase subunit VIA-liver;
DE Short=COX VIa-L;
DE Flags: Precursor;
GN Name=COX6A1; Synonyms=COX6AL;
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 [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Testis, and Uterus;
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 NUCLEOTIDE SEQUENCE [MRNA] OF 3-109.
RC TISSUE=Liver;
RX PubMed=2549515; DOI=10.1093/nar/17.15.6409;
RA Fabrizi G.M., Rizzuto R., Nakase H., Mita S., Kadenbach B., Schon E.A.;
RT "Sequence of a cDNA specifying subunit VIa of human cytochrome c oxidase.";
RL Nucleic Acids Res. 17:6409-6409(1989).
RN [5]
RP PROTEIN SEQUENCE OF 25-36.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [6]
RP INVOLVEMENT IN CMTRID.
RX PubMed=25152455; DOI=10.1016/j.ajhg.2014.07.013;
RA Tamiya G., Makino S., Hayashi M., Abe A., Numakura C., Ueki M., Tanaka A.,
RA Ito C., Toshimori K., Ogawa N., Terashima T., Maegawa H., Yanagisawa D.,
RA Tooyama I., Tada M., Onodera O., Hayasaka K.;
RT "A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-
RT Marie-Tooth disease.";
RL Am. J. Hum. Genet. 95:294-300(2014).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [8]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.90 ANGSTROMS), AND SUBUNIT.
RX PubMed=28844695; DOI=10.1016/j.cell.2017.07.050;
RA Guo R., Zong S., Wu M., Gu J., Yang M.;
RT "Architecture of human mitochondrial respiratory megacomplex I2III2IV2.";
RL Cell 170:1247-1257(2017).
RN [9]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 34-109.
RX PubMed=30030519; DOI=10.1038/s41422-018-0071-1;
RA Zong S., Wu M., Gu J., Liu T., Guo R., Yang M.;
RT "Structure of the intact 14-subunit human cytochrome c oxidase.";
RL Cell Res. 28:1026-1034(2018).
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. {ECO:0000250|UniProtKB:P32799}.
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 (PubMed:30030519). The complex exists as a
CC monomer or a dimer and forms supercomplexes (SCs) in the inner
CC mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I,
CC CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex,
CC complex III, CIII), resulting in different assemblies (supercomplex
CC SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).
CC {ECO:0000269|PubMed:28844695, ECO:0000269|PubMed:30030519}.
CC -!- INTERACTION:
CC P12074; P42858: HTT; NbExp=4; IntAct=EBI-2115950, EBI-466029;
CC P12074; Q9BS40: LXN; NbExp=3; IntAct=EBI-2115950, EBI-1044504;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:30030519}; Single-pass membrane protein
CC {ECO:0000269|PubMed:30030519}.
CC -!- DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, D
CC (CMTRID) [MIM:616039]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later of
CC the distal muscles of the arms. Recessive intermediate forms of
CC Charcot-Marie-Tooth disease are characterized by clinical and
CC pathologic features intermediate between demyelinating and axonal
CC peripheral neuropathies, and motor median nerve conduction velocities
CC ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:25152455}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the cytochrome c oxidase subunit 6A family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA33392.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK312009; BAG34947.1; -; mRNA.
DR EMBL; AL021546; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007723; AAH07723.1; -; mRNA.
DR EMBL; BC070186; AAH70186.1; -; mRNA.
DR EMBL; BC107861; AAI07862.1; -; mRNA.
DR EMBL; X15341; CAA33392.1; ALT_FRAME; mRNA.
DR CCDS; CCDS9197.1; -.
DR RefSeq; NP_004364.2; NM_004373.3.
DR PDB; 5Z62; EM; 3.60 A; G=34-108.
DR PDBsum; 5Z62; -.
DR AlphaFoldDB; P12074; -.
DR SMR; P12074; -.
DR BioGRID; 107730; 52.
DR ComplexPortal; CPX-6123; Mitochondrial respiratory chain complex IV.
DR IntAct; P12074; 17.
DR STRING; 9606.ENSP00000229379; -.
DR iPTMnet; P12074; -.
DR PhosphoSitePlus; P12074; -.
DR BioMuta; COX6A1; -.
DR DMDM; 6166030; -.
DR SWISS-2DPAGE; P12074; -.
DR EPD; P12074; -.
DR jPOST; P12074; -.
DR MassIVE; P12074; -.
DR MaxQB; P12074; -.
DR PaxDb; P12074; -.
DR PeptideAtlas; P12074; -.
DR PRIDE; P12074; -.
DR ProteomicsDB; 52823; -.
DR TopDownProteomics; P12074; -.
DR Antibodypedia; 45523; 362 antibodies from 29 providers.
DR DNASU; 1337; -.
DR Ensembl; ENST00000229379.3; ENSP00000229379.2; ENSG00000111775.3.
DR GeneID; 1337; -.
DR KEGG; hsa:1337; -.
DR MANE-Select; ENST00000229379.3; ENSP00000229379.2; NM_004373.4; NP_004364.2.
DR UCSC; uc001tyf.2; human.
DR CTD; 1337; -.
DR DisGeNET; 1337; -.
DR GeneCards; COX6A1; -.
DR HGNC; HGNC:2277; COX6A1.
DR HPA; ENSG00000111775; Low tissue specificity.
DR MalaCards; COX6A1; -.
DR MIM; 602072; gene.
DR MIM; 616039; phenotype.
DR neXtProt; NX_P12074; -.
DR OpenTargets; ENSG00000111775; -.
DR Orphanet; 435998; Autosomal recessive intermediate Charcot-Marie-Tooth disease type D.
DR PharmGKB; PA26794; -.
DR VEuPathDB; HostDB:ENSG00000111775; -.
DR eggNOG; KOG3469; Eukaryota.
DR GeneTree; ENSGT00940000154612; -.
DR HOGENOM; CLU_122515_1_1_1; -.
DR InParanoid; P12074; -.
DR OMA; GYEGHDE; -.
DR OrthoDB; 1591077at2759; -.
DR PhylomeDB; P12074; -.
DR TreeFam; TF105064; -.
DR BioCyc; MetaCyc:HS03462-MON; -.
DR PathwayCommons; P12074; -.
DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-HSA-611105; Respiratory electron transport.
DR Reactome; R-HSA-9707564; Cytoprotection by HMOX1.
DR SignaLink; P12074; -.
DR SIGNOR; P12074; -.
DR UniPathway; UPA00705; -.
DR BioGRID-ORCS; 1337; 119 hits in 1039 CRISPR screens.
DR ChiTaRS; COX6A1; human.
DR GeneWiki; COX6A1; -.
DR GenomeRNAi; 1337; -.
DR Pharos; P12074; Tbio.
DR PRO; PR:P12074; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P12074; protein.
DR Bgee; ENSG00000111775; Expressed in prefrontal cortex and 99 other tissues.
DR ExpressionAtlas; P12074; baseline and differential.
DR Genevisible; P12074; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0031966; C:mitochondrial membrane; IDA:ComplexPortal.
DR GO; GO:0005751; C:mitochondrial respiratory chain complex IV; IPI:ComplexPortal.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
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:0045333; P:cellular respiration; IC:ComplexPortal.
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 3D-structure; Charcot-Marie-Tooth disease; Direct protein sequencing;
KW Membrane; Mitochondrion; Mitochondrion inner membrane; Neurodegeneration;
KW Neuropathy; Oxidoreductase; Reference proteome; Transit peptide;
KW Transmembrane; Transmembrane helix.
FT TRANSIT 1..24
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:1286669"
FT CHAIN 25..109
FT /note="Cytochrome c oxidase subunit 6A1, mitochondrial"
FT /id="PRO_0000006119"
FT TOPO_DOM 25..34
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000269|PubMed:30030519"
FT TRANSMEM 35..59
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:P07471"
FT TOPO_DOM 60..109
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000269|PubMed:30030519"
SQ SEQUENCE 109 AA; 12155 MW; 0040F47CECE767B1 CRC64;
MAVVGVSSVS RLLGRSRPQL GRPMSSGAHG EEGSARMWKT LTFFVALPGV AVSMLNVYLK
SHHGEHERPE FIAYPHLRIR TKPFPWGDGN HTLFHNPHVN PLPTGYEDE
