ID   UCP4_HUMAN              Reviewed;         323 AA.
AC   O95847; F5GWR4; Q5VTS9; Q8N518;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   27-MAR-2024, entry version 174.
DE   RecName: Full=Mitochondrial uncoupling protein 4;
DE            Short=UCP 4;
DE   AltName: Full=Solute carrier family 25 member 27;
GN   Name=SLC25A27; Synonyms=UCP4 {ECO:0000303|PubMed:10025957};
GN   ORFNames=UNQ772/PRO1566;
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] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND
RP   TISSUE SPECIFICITY.
RC   TISSUE=Brain;
RX   PubMed=10025957; DOI=10.1016/s0014-5793(98)01713-x;
RA   Mao W., Yu X.X., Zhong A., Li W., Brush J., Sherwood S.W., Adams S.H.,
RA   Pan G.;
RT   "UCP4, a novel brain-specific mitochondrial protein that reduces membrane
RT   potential in mammalian cells.";
RL   FEBS Lett. 443:326-330(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX   PubMed=12975309; DOI=10.1101/gr.1293003;
RA   Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA   Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA   Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA   Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA   Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA   Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA   Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA   Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT   "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT   identify novel human secreted and transmembrane proteins: a bioinformatics
RT   assessment.";
RL   Genome Res. 13:2265-2270(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=14574404; DOI=10.1038/nature02055;
RA   Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA   Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA   Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA   Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA   Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA   Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA   Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA   Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA   Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA   Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA   French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA   Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA   Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA   Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA   Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA   Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA   Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA   Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA   Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA   Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA   Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA   Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA   Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA   Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA   Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA   West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA   Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA   Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA   Rogers J., Beck S.;
RT   "The DNA sequence and analysis of human chromosome 6.";
RL   Nature 425:805-811(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton 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   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT VAL-145.
RC   TISSUE=Prostate;
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   FUNCTION, TRANSPORTER ACTIVITY, AND ACTIVITY REGULATION.
RX   PubMed=22524567; DOI=10.1021/bi3003378;
RA   Hoang T., Smith M.D., Jelokhani-Niaraki M.;
RT   "Toward understanding the mechanism of ion transport activity of neuronal
RT   uncoupling proteins UCP2, UCP4, and UCP5.";
RL   Biochemistry 51:4004-4014(2012).
RN   [8]
RP   FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND SUBUNIT.
RX   PubMed=26182433; DOI=10.1042/bsr20150130;
RA   Hoang T., Kuljanin M., Smith M.D., Jelokhani-Niaraki M.;
RT   "A biophysical study on molecular physiology of the uncoupling proteins of
RT   the central nervous system.";
RL   Biosci. Rep. 35:0-0(2015).
CC   -!- FUNCTION: Facilitates proton transport across the inner mitochondrial
CC       membrane and may dissipate excessive proton gradient associated with
CC       oxidative and metabolic stress at neuronal synapses. Regulates
CC       glutamate-induced proton conductance in astrocytes, shifting the energy
CC       metabolism toward aerobic glycolysis and lactate transfer to neurons
CC       for ATP synthesis. Can transport chloride ions with lower efficiency.
CC       The transport mechanism remains to be elucidated.
CC       {ECO:0000250|UniProtKB:Q9D6D0, ECO:0000269|PubMed:10025957,
CC       ECO:0000269|PubMed:22524567, ECO:0000269|PubMed:26182433}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378;
CC         Evidence={ECO:0000269|PubMed:22524567, ECO:0000269|PubMed:26182433};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823,
CC         ChEBI:CHEBI:17996; Evidence={ECO:0000269|PubMed:22524567,
CC         ECO:0000269|PubMed:26182433};
CC   -!- ACTIVITY REGULATION: Proton conductance is up-regulated by unsaturated
CC       long-chain fatty acids and inhibited by purine nucleotides ATP and ADP.
CC       The transport of chloride ions is partially inhibited by long-chain
CC       fatty acids. {ECO:0000269|PubMed:22524567,
CC       ECO:0000269|PubMed:26182433}.
CC   -!- SUBUNIT: Homotetramer. {ECO:0000269|PubMed:26182433}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC       {ECO:0000269|PubMed:10025957}; Multi-pass membrane protein
CC       {ECO:0000255}. Note=Localizes to neuronal cell body and processes.
CC       Within mitochondrial inner membrane, it is mainly observed in the inner
CC       boundary membrane locally separated from F(1)F(0) ATP synthase, which
CC       is preferentially localized in cristae. {ECO:0000250|UniProtKB:Q9D6D0}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=O95847-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=O95847-2; Sequence=VSP_045916;
CC   -!- TISSUE SPECIFICITY: Found in adult and fetal brain. Present in most of
CC       the brain tissues, with low levels in spinal chord, corpus callosum and
CC       substantia nigra. {ECO:0000269|PubMed:10025957}.
CC   -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) 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; AF110532; AAD16995.1; -; mRNA.
DR   EMBL; AY358711; AAQ89951.1; -; mRNA.
DR   EMBL; AK291427; BAF84116.1; -; mRNA.
DR   EMBL; AL591242; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471081; EAX04299.1; -; Genomic_DNA.
DR   EMBL; BC033091; AAH33091.1; -; mRNA.
DR   CCDS; CCDS43470.1; -. [O95847-1]
DR   CCDS; CCDS56431.1; -. [O95847-2]
DR   RefSeq; NP_001190980.1; NM_001204051.1.
DR   RefSeq; NP_001190981.1; NM_001204052.1. [O95847-2]
DR   RefSeq; NP_004268.3; NM_004277.4. [O95847-1]
DR   AlphaFoldDB; O95847; -.
DR   SMR; O95847; -.
DR   BioGRID; 114866; 2.
DR   IntAct; O95847; 3.
DR   STRING; 9606.ENSP00000360398; -.
DR   TCDB; 2.A.29.24.3; the mitochondrial carrier (mc) family.
DR   iPTMnet; O95847; -.
DR   PhosphoSitePlus; O95847; -.
DR   BioMuta; SLC25A27; -.
DR   jPOST; O95847; -.
DR   MassIVE; O95847; -.
DR   PaxDb; 9606-ENSP00000360398; -.
DR   PeptideAtlas; O95847; -.
DR   ProteomicsDB; 24193; -.
DR   ProteomicsDB; 51088; -. [O95847-1]
DR   Antibodypedia; 4016; 104 antibodies from 23 providers.
DR   DNASU; 9481; -.
DR   Ensembl; ENST00000371347.10; ENSP00000360398.3; ENSG00000153291.16. [O95847-1]
DR   Ensembl; ENST00000411689.6; ENSP00000412024.2; ENSG00000153291.16. [O95847-2]
DR   GeneID; 9481; -.
DR   KEGG; hsa:9481; -.
DR   MANE-Select; ENST00000371347.10; ENSP00000360398.3; NM_004277.5; NP_004268.3.
DR   UCSC; uc003oyg.3; human. [O95847-1]
DR   AGR; HGNC:21065; -.
DR   CTD; 9481; -.
DR   DisGeNET; 9481; -.
DR   GeneCards; SLC25A27; -.
DR   HGNC; HGNC:21065; SLC25A27.
DR   HPA; ENSG00000153291; Low tissue specificity.
DR   MIM; 613725; gene.
DR   neXtProt; NX_O95847; -.
DR   OpenTargets; ENSG00000153291; -.
DR   PharmGKB; PA134970102; -.
DR   VEuPathDB; HostDB:ENSG00000153291; -.
DR   eggNOG; KOG0753; Eukaryota.
DR   GeneTree; ENSGT00940000160098; -.
DR   HOGENOM; CLU_015166_14_2_1; -.
DR   InParanoid; O95847; -.
DR   OMA; FPFWKAV; -.
DR   OrthoDB; 5488094at2759; -.
DR   PhylomeDB; O95847; -.
DR   TreeFam; TF354328; -.
DR   PathwayCommons; O95847; -.
DR   Reactome; R-HSA-167826; The fatty acid cycling model.
DR   Reactome; R-HSA-167827; The proton buffering model.
DR   SignaLink; O95847; -.
DR   SIGNOR; O95847; -.
DR   BioGRID-ORCS; 9481; 11 hits in 1154 CRISPR screens.
DR   ChiTaRS; SLC25A27; human.
DR   GeneWiki; SLC25A27; -.
DR   GenomeRNAi; 9481; -.
DR   Pharos; O95847; Tbio.
DR   PRO; PR:O95847; -.
DR   Proteomes; UP000005640; Chromosome 6.
DR   RNAct; O95847; Protein.
DR   Bgee; ENSG00000153291; Expressed in mucosa of stomach and 172 other cell types or tissues.
DR   ExpressionAtlas; O95847; baseline and differential.
DR   GO; GO:0045177; C:apical part of cell; IEA:Ensembl.
DR   GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR   GO; GO:0031966; C:mitochondrial membrane; IDA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR   GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR   GO; GO:0015108; F:chloride transmembrane transporter activity; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0015078; F:proton transmembrane transporter activity; IDA:UniProtKB.
DR   GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR   GO; GO:0048839; P:inner ear development; IEA:Ensembl.
DR   GO; GO:0035356; P:intracellular triglyceride homeostasis; IEA:Ensembl.
DR   GO; GO:0051562; P:negative regulation of mitochondrial calcium ion concentration; IEA:Ensembl.
DR   GO; GO:0010917; P:negative regulation of mitochondrial membrane potential; IEA:Ensembl.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR   GO; GO:0046324; P:regulation of glucose import; IEA:Ensembl.
DR   GO; GO:0009409; P:response to cold; IBA:GO_Central.
DR   Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1.
DR   InterPro; IPR018108; Mitochondrial_sb/sol_carrier.
DR   InterPro; IPR023395; Mt_carrier_dom_sf.
DR   PANTHER; PTHR45618; MITOCHONDRIAL DICARBOXYLATE CARRIER-RELATED; 1.
DR   PANTHER; PTHR45618:SF8; MITOCHONDRIAL UNCOUPLING PROTEIN 4; 1.
DR   Pfam; PF00153; Mito_carr; 3.
DR   SUPFAM; SSF103506; Mitochondrial carrier; 1.
DR   PROSITE; PS50920; SOLCAR; 3.
DR   Genevisible; O95847; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Membrane; Mitochondrion;
KW   Mitochondrion inner membrane; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport.
FT   CHAIN           1..323
FT                   /note="Mitochondrial uncoupling protein 4"
FT                   /id="PRO_0000090676"
FT   TRANSMEM        23..40
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        88..109
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        127..144
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        195..212
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        229..248
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        288..311
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000255"
FT   REPEAT          21..115
FT                   /note="Solcar 1"
FT   REPEAT          125..217
FT                   /note="Solcar 2"
FT   REPEAT          226..317
FT                   /note="Solcar 3"
FT   VAR_SEQ         236..323
FT                   /note="LCSGLVASILGTPADVIKSRIMNQPRDKQGRGLLYKSSTDCLIQAVQGEGFM
FT                   SLYKGFLPSWLRMTPWSMVFWLTYEKIREMSGVSPF -> DLVGSHKAIQ (in
FT                   isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_045916"
FT   VARIANT         145
FT                   /note="A -> V (in dbSNP:rs17853162)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_069101"
FT   VARIANT         197
FT                   /note="I -> T (in dbSNP:rs35884480)"
FT                   /id="VAR_050137"
SQ   SEQUENCE   323 AA;  36064 MW;  4C54A56BB10333ED CRC64;
     MSVPEEEERL LPLTQRWPRA SKFLLSGCAA TVAELATFPL DLTKTRLQMQ GEAALARLGD
     GARESAPYRG MVRTALGIIE EEGFLKLWQG VTPAIYRHVV YSGGRMVTYE HLREVVFGKS
     EDEHYPLWKS VIGGMMAGVI GQFLANPTDL VKVQMQMEGK RKLEGKPLRF RGVHHAFAKI
     LAEGGIRGLW AGWVPNIQRA ALVNMGDLTT YDTVKHYLVL NTPLEDNIMT HGLSSLCSGL
     VASILGTPAD VIKSRIMNQP RDKQGRGLLY KSSTDCLIQA VQGEGFMSLY KGFLPSWLRM
     TPWSMVFWLT YEKIREMSGV SPF
//