NDUA4_HUMAN
ID NDUA4_HUMAN Reviewed; 81 AA.
AC O00483; A4D109; Q6FHN5;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Cytochrome c oxidase subunit NDUFA4;
DE AltName: Full=Complex I-MLRQ;
DE Short=CI-MLRQ;
DE AltName: Full=NADH-ubiquinone oxidoreductase MLRQ subunit;
GN Name=NDUFA4;
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].
RC TISSUE=Liver;
RX PubMed=9352085; DOI=10.1080/15216549700204471;
RA Kim J.W., Lee Y., Kang H.B., Chose Y.K., Chung T.W., Chang S.Y., Lee K.S.,
RA Choe I.S.;
RT "Cloning of the human cDNA sequence encoding the NADH:ubiquinone
RT oxidoreductase MLRQ subunit.";
RL Biochem. Mol. Biol. Int. 43:669-675(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Kanagarajah D., Raha S., Scherer S., Robinson B.H.;
RT "Genomic sequence, cDNA sequence and chromosomal localization of the NDUFA4
RT human gene coding for the MLRQ subunit of NADH:ubiquinone oxidoreductase
RT and its pseudogene.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
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 MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [6]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
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 [8]
RP INITIAL IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12611891; DOI=10.1074/jbc.c300064200;
RA Murray J., Zhang B., Taylor S.W., Oglesbee D., Fahy E., Marusich M.F.,
RA Ghosh S.S., Capaldi R.A.;
RT "The subunit composition of the human NADH dehydrogenase obtained by rapid
RT one-step immunopurification.";
RL J. Biol. Chem. 278:13619-13622(2003).
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 FUNCTION, AND IDENTIFICATION AS CYTOCHROME C OXIDASE SUBUNIT.
RX PubMed=22902835; DOI=10.1016/j.cmet.2012.07.015;
RA Balsa E., Marco R., Perales-Clemente E., Szklarczyk R., Calvo E.,
RA Landazuri M.O., Enriquez J.A.;
RT "NDUFA4 is a subunit of complex IV of the mammalian electron transport
RT chain.";
RL Cell Metab. 16:378-386(2012).
RN [11]
RP SUBUNIT, SUBCELLULAR LOCATION, AND INVOLVEMENT IN MC4DN21.
RX PubMed=23746447; DOI=10.1016/j.celrep.2013.05.005;
RA Pitceathly R.D., Rahman S., Wedatilake Y., Polke J.M., Cirak S.,
RA Foley A.R., Sailer A., Hurles M.E., Stalker J., Hargreaves I.,
RA Woodward C.E., Sweeney M.G., Muntoni F., Houlden H., Taanman J.W.,
RA Hanna M.G.;
RT "NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit
RT linked to human neurological disease.";
RL Cell Rep. 3:1795-1805(2013).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-66, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [13]
RP IDENTIFICATION BY 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 [14]
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 [15]
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 [16]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 3-81.
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 (PubMed:22902835). NDUFA4 is
CC required for complex IV maintenance (PubMed:22902835).
CC {ECO:0000269|PubMed:22902835}.
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:22902835, PubMed:23746447,
CC PubMed:30030519). The complex exists as a monomer or a dimer and forms
CC supercomplexes (SCs) in the inner mitochondrial membrane with NADH-
CC ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c
CC oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting
CC in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex
CC MCI(2)III(2)IV(2)) (Probable). Interacts with RAB5IF (PubMed:31536960).
CC {ECO:0000269|PubMed:22902835, ECO:0000269|PubMed:23746447,
CC ECO:0000269|PubMed:30030519, ECO:0000269|PubMed:31536960, ECO:0000305}.
CC -!- INTERACTION:
CC O00483; Q92782-2: DPF1; NbExp=3; IntAct=EBI-1049381, EBI-23669343;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:23746447, ECO:0000269|PubMed:30030519}; Single-pass
CC membrane protein {ECO:0000269|PubMed:30030519}.
CC -!- DISEASE: Mitochondrial complex IV deficiency, nuclear type 21 (MC4DN21)
CC [MIM:619065]: An autosomal recessive mitochondrial disorder with onset
CC in infancy. MC4DN21 is characterized by congenital lactic acidosis,
CC encephalopathy, global developmental delay, delayed speech, motor
CC dysfunction, dystonia, and spasticity. Ataxia, peripheral neuropathy,
CC and seizures may also occur. Patient tissues show variably decreased
CC levels and activity of mitochondrial respiratory complex IV.
CC {ECO:0000269|PubMed:23746447}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: During complex IV purifications dissociates from complex
CC IV upon treatment with standard detergent DDM (decyl beta-D-maltoside)
CC in high concentrations (PubMed:22902835, PubMed:23746447).
CC {ECO:0000305|PubMed:22902835, ECO:0000305|PubMed:23746447}.
CC -!- SIMILARITY: Belongs to the complex IV NDUFA4 subunit family.
CC {ECO:0000305}.
CC -!- CAUTION: Was initially believed to be a subunit of the mitochondrial
CC membrane respiratory chain NADH dehydrogenase (complex I).
CC {ECO:0000305|PubMed:12611891}.
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DR EMBL; U94586; AAB52726.1; -; mRNA.
DR EMBL; AF201077; AAF09253.1; -; mRNA.
DR EMBL; CR407618; CAG28546.1; -; mRNA.
DR EMBL; CR541716; CAG46517.1; -; mRNA.
DR EMBL; CH236948; EAL24297.1; -; Genomic_DNA.
DR EMBL; CH471073; EAW93631.1; -; Genomic_DNA.
DR EMBL; BC105295; AAI05296.1; -; mRNA.
DR EMBL; BC101794; AAI01795.1; -; mRNA.
DR EMBL; BC101796; AAI01797.1; -; mRNA.
DR CCDS; CCDS5357.1; -.
DR RefSeq; NP_002480.1; NM_002489.3.
DR PDB; 5Z62; EM; 3.60 A; N=3-81.
DR PDBsum; 5Z62; -.
DR AlphaFoldDB; O00483; -.
DR SMR; O00483; -.
DR BioGRID; 110777; 281.
DR ComplexPortal; CPX-6123; Mitochondrial respiratory chain complex IV.
DR CORUM; O00483; -.
DR IntAct; O00483; 259.
DR MINT; O00483; -.
DR STRING; 9606.ENSP00000339720; -.
DR BindingDB; O00483; -.
DR ChEMBL; CHEMBL2317; -.
DR DrugBank; DB00157; NADH.
DR DrugCentral; O00483; -.
DR GlyGen; O00483; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O00483; -.
DR PhosphoSitePlus; O00483; -.
DR SwissPalm; O00483; -.
DR BioMuta; NDUFA4; -.
DR EPD; O00483; -.
DR jPOST; O00483; -.
DR MassIVE; O00483; -.
DR MaxQB; O00483; -.
DR PaxDb; O00483; -.
DR PeptideAtlas; O00483; -.
DR PRIDE; O00483; -.
DR ProteomicsDB; 47931; -.
DR TopDownProteomics; O00483; -.
DR Antibodypedia; 56007; 150 antibodies from 27 providers.
DR DNASU; 4697; -.
DR Ensembl; ENST00000339600.6; ENSP00000339720.5; ENSG00000189043.10.
DR GeneID; 4697; -.
DR KEGG; hsa:4697; -.
DR MANE-Select; ENST00000339600.6; ENSP00000339720.5; NM_002489.4; NP_002480.1.
DR UCSC; uc003srx.3; human.
DR CTD; 4697; -.
DR DisGeNET; 4697; -.
DR GeneCards; NDUFA4; -.
DR HGNC; HGNC:7687; NDUFA4.
DR HPA; ENSG00000189043; Tissue enhanced (skeletal muscle, tongue).
DR MalaCards; NDUFA4; -.
DR MIM; 603833; gene.
DR MIM; 619065; phenotype.
DR neXtProt; NX_O00483; -.
DR OpenTargets; ENSG00000189043; -.
DR Orphanet; 255241; Leigh syndrome with leukodystrophy.
DR PharmGKB; PA31493; -.
DR VEuPathDB; HostDB:ENSG00000189043; -.
DR eggNOG; ENOG502S65P; Eukaryota.
DR GeneTree; ENSGT00940000154268; -.
DR HOGENOM; CLU_181002_0_0_1; -.
DR InParanoid; O00483; -.
DR OMA; QHKFYSP; -.
DR OrthoDB; 1552648at2759; -.
DR PhylomeDB; O00483; -.
DR TreeFam; TF106383; -.
DR BioCyc; MetaCyc:HS08711-MON; -.
DR PathwayCommons; O00483; -.
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; O00483; -.
DR SIGNOR; O00483; -.
DR BioGRID-ORCS; 4697; 257 hits in 1015 CRISPR screens.
DR ChiTaRS; NDUFA4; human.
DR GenomeRNAi; 4697; -.
DR Pharos; O00483; Tclin.
DR PRO; PR:O00483; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O00483; protein.
DR Bgee; ENSG00000189043; Expressed in heart right ventricle and 207 other tissues.
DR ExpressionAtlas; O00483; baseline and differential.
DR Genevisible; O00483; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0031966; C:mitochondrial membrane; IDA:ComplexPortal.
DR GO; GO:0005747; C:mitochondrial respiratory chain complex I; IDA:UniProtKB.
DR GO; GO:0005751; C:mitochondrial respiratory chain complex IV; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; TAS:ProtInc.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:MGI.
DR GO; GO:0045333; P:cellular respiration; IC:ComplexPortal.
DR GO; GO:0006123; P:mitochondrial electron transport, cytochrome c to oxygen; IC:ComplexPortal.
DR GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; NAS:UniProtKB.
DR GO; GO:1904960; P:positive regulation of cytochrome-c oxidase activity; IMP:UniProtKB.
DR InterPro; IPR010530; B12D.
DR PANTHER; PTHR14256; PTHR14256; 1.
DR Pfam; PF06522; B12D; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Electron transport; Leigh syndrome; Membrane;
KW Mitochondrion; Mitochondrion inner membrane; Phosphoprotein;
KW Primary mitochondrial disease; Reference proteome; Respiratory chain;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..81
FT /note="Cytochrome c oxidase subunit NDUFA4"
FT /id="PRO_0000118821"
FT TOPO_DOM 1..14
FT /note="Mitochondrial matrix"
FT /evidence="ECO:0000269|PubMed:30030519"
FT TRANSMEM 15..37
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:30030519"
FT TOPO_DOM 38..81
FT /note="Mitochondrial intermembrane"
FT /evidence="ECO:0000269|PubMed:30030519"
FT MOD_RES 10
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q62425"
FT MOD_RES 66
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
SQ SEQUENCE 81 AA; 9370 MW; 2FA1D1115EDE24C7 CRC64;
MLRQIIGQAK KHPSLIPLFV FIGTGATGAT LYLLRLALFN PDVCWDRNNP EPWNKLGPND
QYKFYSVNVD YSKLKKERPD F
