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 02-JUN-2021, entry version 182. 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}. 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; 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 SMR; O43181; -. DR BioGRID; 110803; 164. DR ComplexPortal; CPX-577; Mitochondrial respiratory chain complex I. DR CORUM; O43181; -. DR IntAct; O43181; 46. DR MINT; O43181; -. DR STRING; 9606.ENSP00000296684; -. DR BindingDB; O43181; -. DR ChEMBL; CHEMBL2363065; -. DR DrugBank; DB00157; NADH. DR DrugCentral; O43181; -. DR CarbonylDB; O43181; -. 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; 295 antibodies. DR DNASU; 4724; -. DR Ensembl; ENST00000296684; ENSP00000296684; ENSG00000164258. DR GeneID; 4724; -. DR KEGG; hsa:4724; -. 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; Low tissue specificity. 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:ENSG00000164258.11; -. DR eggNOG; KOG3389; Eukaryota. DR GeneTree; ENSGT00390000013835; -. DR HOGENOM; CLU_077196_3_0_1; -. DR InParanoid; O43181; -. DR OMA; DYMQGTI; -. DR OrthoDB; 1507807at2759; -. DR PhylomeDB; O43181; -. DR TreeFam; TF105619; -. DR BioCyc; MetaCyc:ENSG00000164258-MONOMER; -. DR PathwayCommons; O43181; -. DR Reactome; R-HSA-611105; Respiratory electron transport. DR Reactome; R-HSA-6799198; Complex I biogenesis. DR SIGNOR; O43181; -. DR BioGRID-ORCS; 4724; 6 hits in 995 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 quadriceps femoris and 246 other tissues. DR ExpressionAtlas; O43181; baseline and differential. DR Genevisible; O43181; HS. DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome. 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: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; TAS:Reactome. 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: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 //