COX5A_HUMAN
ID COX5A_HUMAN Reviewed; 150 AA.
AC P20674; P30045; Q8TB65;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 2.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Cytochrome c oxidase subunit 5A, mitochondrial;
DE AltName: Full=Cytochrome c oxidase polypeptide Va;
DE Flags: Precursor;
GN Name=COX5A;
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].
RX PubMed=2853101; DOI=10.1016/0378-1119(88)90435-0;
RA Rizzuto R., Nakase H., Zeviani M., Dimauro S., Schon E.A.;
RT "Subunit Va of human and bovine cytochrome c oxidase is highly conserved.";
RL Gene 69:245-256(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=18197981; DOI=10.1186/1471-2148-8-8;
RA Uddin M., Opazo J.C., Wildman D.E., Sherwood C.C., Hof P.R., Goodman M.,
RA Grossman L.I.;
RT "Molecular evolution of the cytochrome c oxidase subunit 5A gene in
RT primates.";
RL BMC Evol. Biol. 8:8-8(2008).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
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 [7]
RP PROTEIN SEQUENCE OF 42-52.
RC TISSUE=Liver;
RX PubMed=8313870; DOI=10.1002/elps.11501401181;
RA Hughes G.J., Frutiger S., Paquet N., Pasquali C., Sanchez J.-C.,
RA Tissot J.-D., Bairoch A., Appel R.D., Hochstrasser D.F.;
RT "Human liver protein map: update 1993.";
RL Electrophoresis 14:1216-1222(1993).
RN [8]
RP PROTEIN SEQUENCE OF 56-64 AND 73-80.
RC TISSUE=Heart;
RX PubMed=7498159; DOI=10.1002/elps.11501601192;
RA Kovalyov L.I., Shishkin S.S., Efimochkin A.S., Kovalyova M.A.,
RA Ershova E.S., Egorov T.A., Musalyamov A.K.;
RT "The major protein expression profile and two-dimensional protein database
RT of human heart.";
RL Electrophoresis 16:1160-1169(1995).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-141, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [11]
RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER TYR-41, AND
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 [12]
RP INTERACTION WITH AFG1L.
RX PubMed=26759378; DOI=10.1042/bj20151029;
RA Cesnekova J., Rodinova M., Hansikova H., Houstek J., Zeman J., Stiburek L.;
RT "The mammalian homologue of yeast Afg1 ATPase (lactation elevated 1)
RT mediates degradation of nuclear-encoded complex IV subunits.";
RL Biochem. J. 473:797-804(2016).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH RAB5IF.
RX PubMed=31536960; DOI=10.1016/j.isci.2019.08.057;
RA Moutaoufik M.T., Malty R., Amin S., Zhang Q., Phanse S., Gagarinova A.,
RA Zilocchi M., Hoell L., Minic Z., Gagarinova M., Aoki H., Stockwell J.,
RA Jessulat M., Goebels F., Broderick K., Scott N.E., Vlasblom J., Musso G.,
RA Prasad B., Lamantea E., Garavaglia B., Rajput A., Murayama K., Okazaki Y.,
RA Foster L.J., Bader G.D., Cayabyab F.S., Babu M.;
RT "Rewiring of the Human Mitochondrial Interactome during Neuronal
RT Reprogramming Reveals Regulators of the Respirasome and Neurogenesis.";
RL IScience 19:1114-1132(2019).
RN [14]
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 [15]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS).
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).
RN [16]
RP INVOLVEMENT IN MC4DN20, VARIANT MC4DN20 CYS-107, AND CHARACTERIZATION OF
RP VARIANT MC4DN20 CYS-107.
RX PubMed=28247525; DOI=10.1002/humu.23210;
RA Baertling F., Al-Murshedi F., Sanchez-Caballero L., Al-Senaidi K.,
RA Joshi N.P., Venselaar H., van den Brand M.A., Nijtmans L.G.,
RA Rodenburg R.J.;
RT "Mutation in mitochondrial complex IV subunit COX5A causes pulmonary
RT arterial hypertension, lactic acidemia and failure to thrive.";
RL Hum. Mutat. 38:692-703(2017).
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 using 4 electrons from cytochrome c in the IMS and 4
CC protons from the mitochondrial matrix. {ECO:0000250|UniProtKB:P00427}.
CC -!- PATHWAY: Energy metabolism; oxidative phosphorylation.
CC {ECO:0000250|UniProtKB:P00427}.
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 Interacts with AFG1L (PubMed:26759378). Interacts with RAB5IF
CC (PubMed:31536960). {ECO:0000269|PubMed:26759378,
CC ECO:0000269|PubMed:28844695, ECO:0000269|PubMed:30030519,
CC ECO:0000269|PubMed:31536960}.
CC -!- INTERACTION:
CC P20674; P05067: APP; NbExp=3; IntAct=EBI-715032, EBI-77613;
CC P20674; Q96B26: EXOSC8; NbExp=3; IntAct=EBI-715032, EBI-371922;
CC P20674; Q15323: KRT31; NbExp=3; IntAct=EBI-715032, EBI-948001;
CC P20674; Q6A162: KRT40; NbExp=3; IntAct=EBI-715032, EBI-10171697;
CC P20674; Q14696: MESD; NbExp=3; IntAct=EBI-715032, EBI-6165891;
CC P20674; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-715032, EBI-9090282;
CC P20674; O95238: SPDEF; NbExp=3; IntAct=EBI-715032, EBI-12811275;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:30030519}; Peripheral membrane protein
CC {ECO:0000269|PubMed:30030519}; Matrix side
CC {ECO:0000269|PubMed:30030519}.
CC -!- DISEASE: Mitochondrial complex IV deficiency, nuclear type 20 (MC4DN20)
CC [MIM:619064]: An autosomal recessive mitochondrial disorder with onset
CC in early infancy. MC4DN20 is characterized by pulmonary arterial
CC hypertension, poor feeding, failure to thrive, hypotonia, delayed
CC development, increased serum lactate and metabolic acidosis. Death in
CC infancy occurs due to cardiorespiratory failure. Patient tissues show
CC variably decreased levels and activity of mitochondrial respiratory
CC complex IV. {ECO:0000269|PubMed:28247525}. Note=The disease may be
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome c oxidase subunit 5A family.
CC {ECO:0000305}.
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DR EMBL; M22760; AAA99220.1; -; mRNA.
DR EMBL; DQ987236; ABK92283.1; -; mRNA.
DR EMBL; DQ987237; ABK92284.1; -; mRNA.
DR EMBL; CR407649; CAG28577.1; -; mRNA.
DR EMBL; AC125435; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471136; EAW99288.1; -; Genomic_DNA.
DR EMBL; BC024240; AAH24240.1; -; mRNA.
DR CCDS; CCDS10273.1; -.
DR PIR; JT0342; OTHU5A.
DR RefSeq; NP_004246.2; NM_004255.3.
DR PDB; 5Z62; EM; 3.60 A; E=42-150.
DR PDBsum; 5Z62; -.
DR AlphaFoldDB; P20674; -.
DR SMR; P20674; -.
DR BioGRID; 114778; 202.
DR ComplexPortal; CPX-6123; Mitochondrial respiratory chain complex IV.
DR CORUM; P20674; -.
DR IntAct; P20674; 68.
DR MINT; P20674; -.
DR STRING; 9606.ENSP00000317780; -.
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 GlyGen; P20674; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P20674; -.
DR PhosphoSitePlus; P20674; -.
DR SwissPalm; P20674; -.
DR BioMuta; COX5A; -.
DR DMDM; 218511986; -.
DR DOSAC-COBS-2DPAGE; P20674; -.
DR OGP; P20674; -.
DR SWISS-2DPAGE; P20674; -.
DR UCD-2DPAGE; P20674; -.
DR EPD; P20674; -.
DR jPOST; P20674; -.
DR MassIVE; P20674; -.
DR MaxQB; P20674; -.
DR PaxDb; P20674; -.
DR PeptideAtlas; P20674; -.
DR PRIDE; P20674; -.
DR ProteomicsDB; 53772; -.
DR TopDownProteomics; P20674; -.
DR Antibodypedia; 27166; 367 antibodies from 32 providers.
DR DNASU; 9377; -.
DR Ensembl; ENST00000322347.11; ENSP00000317780.6; ENSG00000178741.12.
DR Ensembl; ENST00000564811.1; ENSP00000456386.1; ENSG00000178741.12.
DR GeneID; 9377; -.
DR KEGG; hsa:9377; -.
DR MANE-Select; ENST00000322347.11; ENSP00000317780.6; NM_004255.4; NP_004246.2.
DR UCSC; uc002azi.5; human.
DR CTD; 9377; -.
DR DisGeNET; 9377; -.
DR GeneCards; COX5A; -.
DR HGNC; HGNC:2267; COX5A.
DR HPA; ENSG00000178741; Tissue enhanced (heart muscle, skeletal muscle, tongue).
DR MalaCards; COX5A; -.
DR MIM; 603773; gene.
DR MIM; 619064; phenotype.
DR neXtProt; NX_P20674; -.
DR OpenTargets; ENSG00000178741; -.
DR Orphanet; 254905; Isolated cytochrome C oxidase deficiency.
DR PharmGKB; PA26784; -.
DR VEuPathDB; HostDB:ENSG00000178741; -.
DR eggNOG; KOG4077; Eukaryota.
DR GeneTree; ENSGT00390000001424; -.
DR HOGENOM; CLU_099086_1_1_1; -.
DR InParanoid; P20674; -.
DR OMA; DPHHEES; -.
DR OrthoDB; 1286549at2759; -.
DR PhylomeDB; P20674; -.
DR TreeFam; TF105062; -.
DR BioCyc; MetaCyc:HS11312-MON; -.
DR PathwayCommons; P20674; -.
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; P20674; -.
DR SIGNOR; P20674; -.
DR UniPathway; UPA00705; -.
DR BioGRID-ORCS; 9377; 413 hits in 1083 CRISPR screens.
DR ChiTaRS; COX5A; human.
DR GenomeRNAi; 9377; -.
DR Pharos; P20674; Tbio.
DR PRO; PR:P20674; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P20674; protein.
DR Bgee; ENSG00000178741; Expressed in heart right ventricle and 200 other tissues.
DR ExpressionAtlas; P20674; baseline and differential.
DR Genevisible; P20674; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:CAFA.
DR GO; GO:0031966; C:mitochondrial membrane; IDA:ComplexPortal.
DR GO; GO:0005751; C:mitochondrial respiratory chain complex IV; IDA:UniProtKB.
DR GO; GO:0004129; F:cytochrome-c oxidase activity; TAS:ProtInc.
DR GO; GO:0009055; F:electron transfer activity; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0045333; P:cellular respiration; IC:ComplexPortal.
DR GO; GO:0006123; P:mitochondrial electron transport, cytochrome c to oxygen; IBA:GO_Central.
DR CDD; cd00923; Cyt_c_Oxidase_Va; 1.
DR Gene3D; 1.25.40.40; -; 1.
DR InterPro; IPR003204; Cyt_c_oxidase_su5A/6.
DR InterPro; IPR036545; Cyt_c_oxidase_su5A/6_sf.
DR PANTHER; PTHR14200; PTHR14200; 1.
DR Pfam; PF02284; COX5A; 1.
DR SUPFAM; SSF48479; SSF48479; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Direct protein sequencing; Disease variant;
KW Heme; Iron; Membrane; Metal-binding; Mitochondrion;
KW Mitochondrion inner membrane; Phosphoprotein;
KW Primary mitochondrial disease; Reference proteome; Transit peptide.
FT TRANSIT 1..41
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:8313870,
FT ECO:0007744|PubMed:25944712"
FT CHAIN 42..150
FT /note="Cytochrome c oxidase subunit 5A, mitochondrial"
FT /id="PRO_0000006100"
FT MOD_RES 87
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P12787"
FT MOD_RES 113
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P12787"
FT MOD_RES 141
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VARIANT 107
FT /note="R -> C (in MC4DN20; decreased protein abundance in
FT patient fibroblasts; decreased proteins abundance of
FT mitochondrial respiratory chain complex IV in patient
FT fibroblasts; no effect on respiratory chain complex IV
FT assembly in patient fibroblasts; increased protein
FT abundance of S1 complex IV intermediate in patient
FT fibroblasts)"
FT /evidence="ECO:0000269|PubMed:28247525"
FT /id="VAR_078264"
FT CONFLICT 105
FT /note="T -> L (in Ref. 1; AAA99220)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 150 AA; 16762 MW; 104DAF468BD302FC CRC64;
MLGAALRRCA VAATTRADPR GLLHSARTPG PAVAIQSVRC YSHGSQETDE EFDARWVTYF
NKPDIDAWEL RKGINTLVTY DMVPEPKIID AALRACRRLN DFASTVRILE VVKDKAGPHK
EIYPYVIQEL RPTLNELGIS TPEELGLDKV
