NDUS4_HUMAN
ID NDUS4_HUMAN Reviewed; 175 AA.
AC O43181; Q9BS69;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial;
DE AltName: Full=Complex I-18 kDa;
DE Short=CI-18 kDa;
DE AltName: Full=Complex I-AQDQ;
DE Short=CI-AQDQ;
DE AltName: Full=NADH-ubiquinone oxidoreductase 18 kDa subunit;
DE Flags: Precursor;
GN Name=NDUFS4;
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], FUNCTION, AND INVOLVEMENT IN MC1DN1.
RX PubMed=9463323; DOI=10.1086/301716;
RA van den Heuvel L., Ruitenbeek W., Smeets R., Gelman-Kohan Z., Elpeleg O.,
RA Loeffen J., Trijbels F., Mariman E., de Bruijn D., Smeitink J.;
RT "Demonstration of a new pathogenic mutation in human complex I deficiency:
RT a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit.";
RL Am. J. Hum. Genet. 62:262-268(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Urinary bladder;
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 [3]
RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANT MC1DN1 15-TRP--LYS-175 DEL.
RX PubMed=11181577; DOI=10.1093/hmg/10.5.529;
RA Petruzzella V., Vergari R., Puzziferri I., Boffoli D., Lamantea E.,
RA Zeviani M., Papa S.;
RT "A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit
RT of complex I abolishes assembly and activity of the complex in a patient
RT with Leigh-like syndrome.";
RL Hum. Mol. Genet. 10:529-535(2001).
RN [4]
RP INVOLVEMENT IN MC1DN1.
RX PubMed=12616398; DOI=10.1007/s00439-002-0884-2;
RA Benit P., Steffann J., Lebon S., Chretien D., Kadhom N., de Lonlay P.,
RA Goldenberg A., Dumez Y., Dommergues M., Rustin P., Munnich A., Roetig A.;
RT "Genotyping microsatellite DNA markers at putative disease loci in
RT inbred/multiplex families with respiratory chain complex I deficiency
RT allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the
RT NDUFS4 gene in Leigh syndrome.";
RL Hum. Genet. 112:563-566(2003).
RN [5]
RP IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX, FUNCTION,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
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 [6]
RP INVOLVEMENT IN MC1DN1.
RX PubMed=19107570; DOI=10.1007/s10545-008-1049-9;
RA Anderson S.L., Chung W.K., Frezzo J., Papp J.C., Ekstein J., DiMauro S.,
RA Rubin B.Y.;
RT "A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish
RT family.";
RL J. Inherit. Metab. Dis. 31:S461-S467(2008).
RN [7]
RP PHOSPHORYLATION AT SER-173, AND MUTAGENESIS OF SER-173.
RX PubMed=20433953; DOI=10.1016/j.mito.2010.04.005;
RA De Rasmo D., Palmisano G., Scacco S., Technikova-Dobrova Z., Panelli D.,
RA Cocco T., Sardanelli A.M., Gnoni A., Micelli L., Trani A., Di Luccia A.,
RA Papa S.;
RT "Phosphorylation pattern of the NDUFS4 subunit of complex I of the
RT mammalian respiratory chain.";
RL Mitochondrion 10:464-471(2010).
RN [8]
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 [9]
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 [10]
RP IDENTIFICATION IN THE NADH-UBIQUINONE OXIDOREDUCTASE COMPLEX.
RX PubMed=27626371; DOI=10.1038/nature19754;
RA Stroud D.A., Surgenor E.E., Formosa L.E., Reljic B., Frazier A.E.,
RA Dibley M.G., Osellame L.D., Stait T., Beilharz T.H., Thorburn D.R.,
RA Salim A., Ryan M.T.;
RT "Accessory subunits are integral for assembly and function of human
RT mitochondrial complex I.";
RL Nature 538:123-126(2016).
RN [11]
RP INTERACTION WITH TOMM40 AND BCAP31, AND SUBCELLULAR LOCATION.
RX PubMed=31206022; DOI=10.1126/sciadv.aaw1386;
RA Namba T.;
RT "BAP31 regulates mitochondrial function via interaction with Tom40 within
RT ER-mitochondria contact sites.";
RL Sci. Adv. 5:eaaw1386-eaaw1386(2019).
RN [12]
RP VARIANTS MC1DN1 97-TRP--LYS-175 DEL AND 106-ARG--LYS-175 DEL.
RX PubMed=10944442; DOI=10.1006/bbrc.2000.3257;
RA Budde S.M., van den Heuvel L.P., Janssen A.J., Smeets R.J., Buskens C.A.,
RA DeMeirleir L., Van Coster R., Baethmann M., Voit T., Trijbels J.M.,
RA Smeitink J.A.;
RT "Combined enzymatic complex I and III deficiency associated with mutations
RT in the nuclear encoded NDUFS4 gene.";
RL Biochem. Biophys. Res. Commun. 275:63-68(2000).
RN [13]
RP VARIANT MC1DN1 15-TRP--LYS-175 DEL.
RX PubMed=15975579; DOI=10.1016/j.febslet.2005.05.035;
RA Petruzzella V., Panelli D., Torraco A., Stella A., Papa S.;
RT "Mutations in the NDUFS4 gene of mitochondrial complex I alter stability of
RT the splice variants.";
RL FEBS Lett. 579:3770-3776(2005).
RN [14]
RP VARIANT MC1DN1 HIS-119.
RX PubMed=19364667; DOI=10.1016/j.ymgme.2009.03.002;
RA Leshinsky-Silver E., Lebre A.S., Minai L., Saada A., Steffann J., Cohen S.,
RA Roetig A., Munnich A., Lev D., Lerman-Sagie T.;
RT "NDUFS4 mutations cause Leigh syndrome with predominant brainstem
RT involvement.";
RL Mol. Genet. Metab. 97:185-189(2009).
CC -!- FUNCTION: Accessory subunit of the mitochondrial membrane respiratory
CC chain NADH dehydrogenase (Complex I), that is believed not to be
CC involved in catalysis. Complex I functions in the transfer of electrons
CC from NADH to the respiratory chain. The immediate electron acceptor for
CC the enzyme is believed to be ubiquinone. {ECO:0000269|PubMed:11181577,
CC ECO:0000269|PubMed:12611891, ECO:0000269|PubMed:9463323}.
CC -!- SUBUNIT: Mammalian complex I is composed of 45 different subunits. This
CC is a component of the iron-sulfur (IP) fragment of the enzyme.
CC Interacts with BCAP31 and TOMM40; the interaction mediates its
CC translocation to the mitochondria; the interaction with BCAP31 is
CC direct (PubMed:31206022). {ECO:0000269|PubMed:12611891,
CC ECO:0000269|PubMed:27626371, ECO:0000269|PubMed:31206022}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:11181577, ECO:0000269|PubMed:12611891,
CC ECO:0000269|PubMed:31206022}; Peripheral membrane protein
CC {ECO:0000269|PubMed:12611891}; Matrix side
CC {ECO:0000269|PubMed:12611891}. Note=The interaction with BCAP31
CC mediates mitochondria localization. {ECO:0000269|PubMed:31206022}.
CC -!- DISEASE: Mitochondrial complex I deficiency, nuclear type 1 (MC1DN1)
CC [MIM:252010]: A form of mitochondrial complex I deficiency, the most
CC common biochemical signature of mitochondrial disorders, a group of
CC highly heterogeneous conditions characterized by defective oxidative
CC phosphorylation, which collectively affects 1 in 5-10000 live births.
CC Clinical disorders have variable severity, ranging from lethal neonatal
CC disease to adult-onset neurodegenerative disorders. Phenotypes include
CC macrocephaly with progressive leukodystrophy, non-specific
CC encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh
CC syndrome, Leber hereditary optic neuropathy, and some forms of
CC Parkinson disease. {ECO:0000269|PubMed:10944442,
CC ECO:0000269|PubMed:11181577, ECO:0000269|PubMed:12616398,
CC ECO:0000269|PubMed:15975579, ECO:0000269|PubMed:19107570,
CC ECO:0000269|PubMed:19364667, ECO:0000269|PubMed:9463323}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the complex I NDUFS4 subunit family.
CC {ECO:0000305}.
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DR EMBL; AF020351; AAB87865.1; -; mRNA.
DR EMBL; BC005270; AAH05270.1; -; mRNA.
DR CCDS; CCDS3960.1; -.
DR RefSeq; NP_002486.1; NM_002495.3.
DR PDB; 5XTB; EM; 3.40 A; L=58-175.
DR PDB; 5XTD; EM; 3.70 A; L=58-175.
DR PDB; 5XTH; EM; 3.90 A; L=58-175.
DR PDB; 5XTI; EM; 17.40 A; BL/L=58-175.
DR PDBsum; 5XTB; -.
DR PDBsum; 5XTD; -.
DR PDBsum; 5XTH; -.
DR PDBsum; 5XTI; -.
DR AlphaFoldDB; O43181; -.
DR SMR; O43181; -.
DR BioGRID; 110803; 187.
DR ComplexPortal; CPX-577; Mitochondrial respiratory chain complex I.
DR CORUM; O43181; -.
DR IntAct; O43181; 48.
DR MINT; O43181; -.
DR STRING; 9606.ENSP00000296684; -.
DR BindingDB; O43181; -.
DR ChEMBL; CHEMBL2363065; -.
DR DrugBank; DB00157; NADH.
DR DrugCentral; O43181; -.
DR CarbonylDB; O43181; -.
DR GlyGen; O43181; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; O43181; -.
DR PhosphoSitePlus; O43181; -.
DR BioMuta; NDUFS4; -.
DR UCD-2DPAGE; O43181; -.
DR EPD; O43181; -.
DR jPOST; O43181; -.
DR MassIVE; O43181; -.
DR MaxQB; O43181; -.
DR PaxDb; O43181; -.
DR PeptideAtlas; O43181; -.
DR PRIDE; O43181; -.
DR ProteomicsDB; 48793; -.
DR TopDownProteomics; O43181; -.
DR Antibodypedia; 1269; 303 antibodies from 34 providers.
DR DNASU; 4724; -.
DR Ensembl; ENST00000296684.10; ENSP00000296684.5; ENSG00000164258.12.
DR GeneID; 4724; -.
DR KEGG; hsa:4724; -.
DR MANE-Select; ENST00000296684.10; ENSP00000296684.5; NM_002495.4; NP_002486.1.
DR UCSC; uc003jpe.3; human.
DR CTD; 4724; -.
DR DisGeNET; 4724; -.
DR GeneCards; NDUFS4; -.
DR GeneReviews; NDUFS4; -.
DR HGNC; HGNC:7711; NDUFS4.
DR HPA; ENSG00000164258; Tissue enhanced (tongue).
DR MalaCards; NDUFS4; -.
DR MIM; 252010; phenotype.
DR MIM; 602694; gene.
DR neXtProt; NX_O43181; -.
DR OpenTargets; ENSG00000164258; -.
DR Orphanet; 2609; Isolated complex I deficiency.
DR Orphanet; 255241; Leigh syndrome with leukodystrophy.
DR PharmGKB; PA31521; -.
DR VEuPathDB; HostDB:ENSG00000164258; -.
DR eggNOG; KOG3389; Eukaryota.
DR GeneTree; ENSGT00390000013835; -.
DR HOGENOM; CLU_077196_3_0_1; -.
DR InParanoid; O43181; -.
DR OMA; GTIMKFD; -.
DR OrthoDB; 1507807at2759; -.
DR PhylomeDB; O43181; -.
DR TreeFam; TF105619; -.
DR BioCyc; MetaCyc:ENSG00000164258-MON; -.
DR PathwayCommons; O43181; -.
DR Reactome; R-HSA-611105; Respiratory electron transport.
DR Reactome; R-HSA-6799198; Complex I biogenesis.
DR SignaLink; O43181; -.
DR SIGNOR; O43181; -.
DR BioGRID-ORCS; 4724; 14 hits in 1079 CRISPR screens.
DR ChiTaRS; NDUFS4; human.
DR GeneWiki; NDUFS4; -.
DR GenomeRNAi; 4724; -.
DR Pharos; O43181; Tclin.
DR PRO; PR:O43181; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O43181; protein.
DR Bgee; ENSG00000164258; Expressed in calcaneal tendon and 214 other tissues.
DR ExpressionAtlas; O43181; baseline and differential.
DR Genevisible; O43181; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:ComplexPortal.
DR GO; GO:0005747; C:mitochondrial respiratory chain complex I; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0008137; F:NADH dehydrogenase (ubiquinone) activity; IMP:UniProtKB.
DR GO; GO:0009060; P:aerobic respiration; IC:ComplexPortal.
DR GO; GO:0007420; P:brain development; IMP:UniProtKB.
DR GO; GO:0045333; P:cellular respiration; IMP:UniProtKB.
DR GO; GO:0006120; P:mitochondrial electron transport, NADH to ubiquinone; NAS:UniProtKB.
DR GO; GO:0032981; P:mitochondrial respiratory chain complex I assembly; IMP:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:UniProtKB.
DR GO; GO:0042776; P:proton motive force-driven mitochondrial ATP synthesis; IC:ComplexPortal.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:UniProtKB.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IMP:MGI.
DR GO; GO:0051591; P:response to cAMP; IMP:UniProtKB.
DR Gene3D; 3.30.160.190; -; 1.
DR InterPro; IPR006885; NADH_UbQ_FeS_4_mit.
DR InterPro; IPR038532; NDUFS4-like_sf.
DR PANTHER; PTHR12219; PTHR12219; 1.
DR Pfam; PF04800; ETC_C1_NDUFA4; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Electron transport; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Phosphoprotein;
KW Primary mitochondrial disease; Reference proteome; Respiratory chain;
KW Transit peptide; Transport.
FT TRANSIT 1..42
FT /note="Mitochondrion"
FT /evidence="ECO:0000250"
FT CHAIN 43..175
FT /note="NADH dehydrogenase [ubiquinone] iron-sulfur protein
FT 4, mitochondrial"
FT /id="PRO_0000020038"
FT REGION 151..175
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 160..175
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 173
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:20433953"
FT VARIANT 15..175
FT /note="Missing (in MC1DN1; loss of mitochondrial
FT respiratory complex I; altered nonsense mediated mRNA
FT decay)"
FT /evidence="ECO:0000269|PubMed:11181577,
FT ECO:0000269|PubMed:15975579"
FT /id="VAR_078943"
FT VARIANT 97..175
FT /note="Missing (in MC1DN1)"
FT /evidence="ECO:0000269|PubMed:10944442"
FT /id="VAR_078944"
FT VARIANT 106..175
FT /note="Missing (in MC1DN1)"
FT /evidence="ECO:0000269|PubMed:10944442"
FT /id="VAR_078945"
FT VARIANT 119
FT /note="D -> H (in MC1DN1; dbSNP:rs747359752)"
FT /evidence="ECO:0000269|PubMed:19364667"
FT /id="VAR_078946"
FT VARIANT 174
FT /note="T -> P (in dbSNP:rs1044692)"
FT /id="VAR_012037"
FT MUTAGEN 173
FT /note="S->A: Loss of phosphorylation."
FT /evidence="ECO:0000269|PubMed:20433953"
FT CONFLICT 39
FT /note="T -> S (in Ref. 2; AAH05270)"
FT /evidence="ECO:0000305"
FT TURN 62..64
FT /evidence="ECO:0007829|PDB:5XTB"
FT HELIX 69..74
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 76..80
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 86..88
FT /evidence="ECO:0007829|PDB:5XTB"
FT TURN 92..94
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 95..101
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:5XTB"
FT TURN 110..113
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 115..118
FT /evidence="ECO:0007829|PDB:5XTB"
FT HELIX 120..123
FT /evidence="ECO:0007829|PDB:5XTB"
FT STRAND 125..130
FT /evidence="ECO:0007829|PDB:5XTB"
FT HELIX 131..141
FT /evidence="ECO:0007829|PDB:5XTB"
FT HELIX 161..163
FT /evidence="ECO:0007829|PDB:5XTB"
FT TURN 166..169
FT /evidence="ECO:0007829|PDB:5XTB"
SQ SEQUENCE 175 AA; 20108 MW; DE5B51DBDD76231E CRC64;
MAAVSMSVVL RQTLWRRRAV AVAALSVSRV PTRSLRTSTW RLAQDQTQDT QLITVDEKLD
ITTLTGVPEE HIKTRKVRIF VPARNNMQSG VNNTKKWKME FDTRERWENP LMGWASTADP
LSNMVLTFST KEDAVSFAEK NGWSYDIEER KVPKPKSKSY GANFSWNKRT RVSTK
