S22A4_HUMAN
ID S22A4_HUMAN Reviewed; 551 AA.
AC Q9H015; O14546;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 3.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Solute carrier family 22 member 4;
DE AltName: Full=Ergothioneine transporter;
DE Short=ET transporter;
DE AltName: Full=Organic cation/carnitine transporter 1;
GN Name=SLC22A4; Synonyms=ETT, OCTN1, UT2H;
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], TISSUE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND VARIANTS THR-306 AND PHE-503.
RC TISSUE=Fetal liver;
RX PubMed=9426230; DOI=10.1016/s0014-5793(97)01441-5;
RA Tamai I., Yabuuchi H., Nezu J., Sai Y., Oku A., Shimane M., Tsuji A.;
RT "Cloning and characterization of a novel human pH-dependent organic cation
RT transporter, OCTN1.";
RL FEBS Lett. 419:107-111(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=15795384; DOI=10.1073/pnas.0408624102;
RA Gruendemann D., Harlfinger S., Golz S., Geerts A., Lazar A., Berkels R.,
RA Jung N., Rubbert A., Schoemig E.;
RT "Discovery of the ergothioneine transporter.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:5256-5261(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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 [5]
RP FUNCTION.
RX PubMed=10215651;
RA Yabuuchi H., Tamai I., Nezu J., Sakamoto K., Oku A., Shimane M., Sai Y.,
RA Tsuji A.;
RT "Novel membrane transporter OCTN1 mediates multispecific, bidirectional,
RT and pH-dependent transport of organic cations.";
RL J. Pharmacol. Exp. Ther. 289:768-773(1999).
RN [6]
RP INDUCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN RA.
RX PubMed=14608356; DOI=10.1038/ng1267;
RA Tokuhiro S., Yamada R., Chang X., Suzuki A., Kochi Y., Sawada T.,
RA Suzuki M., Nagasaki M., Ohtsuki M., Ono M., Furukawa H., Nagashima M.,
RA Yoshino S., Mabuchi A., Sekine A., Saito S., Takahashi A., Tsunoda T.,
RA Nakamura Y., Yamamoto K.;
RT "An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic
RT cation transporter, is associated with rheumatoid arthritis.";
RL Nat. Genet. 35:341-348(2003).
RN [7]
RP VARIANTS THR-306 AND GLU-462.
RX PubMed=12436193; DOI=10.1007/s100380200088;
RA Saito S., Iida A., Sekine A., Ogawa C., Kawauchi S., Higuchi S.,
RA Nakamura Y.;
RT "Catalog of 238 variations among six human genes encoding solute carriers
RT (hSLCs) in the Japanese population.";
RL J. Hum. Genet. 47:576-584(2002).
RN [8]
RP CHARACTERIZATION OF VARIANT GLU-462, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15459889; DOI=10.1002/jps.20190;
RA Kawasaki Y., Kato Y., Sai Y., Tsuji A.;
RT "Functional characterization of human organic cation transporter OCTN1
RT single nucleotide polymorphisms in the Japanese population.";
RL J. Pharm. Sci. 93:2920-2926(2004).
RN [9]
RP VARIANT PHE-503, AND TISSUE SPECIFICITY.
RX PubMed=15107849; DOI=10.1038/ng1339;
RA Peltekova V.D., Wintle R.F., Rubin L.A., Amos C.I., Huang Q., Gu X.,
RA Newman B., Van Oene M., Cescon D., Greenberg G., Griffiths A.M.,
RA St George-Hyslop P.H., Siminovitch K.A.;
RT "Functional variants of OCTN cation transporter genes are associated with
RT Crohn disease.";
RL Nat. Genet. 36:471-475(2004).
CC -!- FUNCTION: Sodium-ion dependent, low affinity carnitine transporter.
CC Probably transports one sodium ion with one molecule of carnitine. Also
CC transports organic cations such as tetraethylammonium (TEA) without the
CC involvement of sodium. Relative uptake activity ratio of carnitine to
CC TEA is 1.78. A key substrate of this transporter seems to be
CC ergothioneine (ET). {ECO:0000269|PubMed:10215651,
CC ECO:0000269|PubMed:15795384}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.470 mM for TEA (at 37 degrees Celsius and pH 7.4)
CC {ECO:0000269|PubMed:15459889, ECO:0000269|PubMed:9426230};
CC Vmax=0.974 nmol/min/mg enzyme toward TEA (at 37 degrees Celsius and
CC pH 7.4) {ECO:0000269|PubMed:15459889, ECO:0000269|PubMed:9426230};
CC pH dependence:
CC More active at neutral and alkaline pHs than at acidic pHs.
CC {ECO:0000269|PubMed:15459889, ECO:0000269|PubMed:9426230};
CC -!- SUBUNIT: Interacts with PDZK1. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in whole blood,
CC bone marrow, trachea and fetal liver. Weakly expressed in kidney,
CC skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus,
CC spleen and spinal cord. Highly expressed in intestinal cell types
CC affected by Crohn disease, including epithelial cells. Expressed in
CC CD68 macrophage and CD43 T-cells but not in CD20 B-cells. Predominantly
CC expressed in CD14 cells in peripheral blood mononuclear cells.
CC {ECO:0000269|PubMed:14608356, ECO:0000269|PubMed:15107849,
CC ECO:0000269|PubMed:9426230}.
CC -!- INDUCTION: Overexpressed upon TNF treatment.
CC {ECO:0000269|PubMed:14608356}.
CC -!- DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory
CC disease with autoimmune features and a complex genetic component. It
CC primarily affects the joints and is characterized by inflammatory
CC changes in the synovial membranes and articular structures, widespread
CC fibrinoid degeneration of the collagen fibers in mesenchymal tissues,
CC and by atrophy and rarefaction of bony structures.
CC {ECO:0000269|PubMed:14608356}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the major facilitator (TC 2.A.1) superfamily.
CC Organic cation transporter (TC 2.A.1.19) family. {ECO:0000305}.
CC -!- CAUTION: PubMed:9426230 reported that this protein does not transport
CC carnitine, however, experiments were done with the Phe-503 variant,
CC which affects the ability to transport carnitine. PubMed:15459889
CC showed that, although weakly, it can also transport carnitine at some
CC level. Its function in carnitine transport is therefore unclear.
CC {ECO:0000305}.
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DR EMBL; AB007448; BAA23356.1; -; mRNA.
DR EMBL; Y09881; CAA71007.1; -; mRNA.
DR EMBL; AC008599; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC034220; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC028313; AAH28313.1; -; mRNA.
DR CCDS; CCDS4153.1; -.
DR RefSeq; NP_003050.2; NM_003059.2.
DR AlphaFoldDB; Q9H015; -.
DR SMR; Q9H015; -.
DR BioGRID; 112470; 207.
DR STRING; 9606.ENSP00000200652; -.
DR ChEMBL; CHEMBL2073668; -.
DR DrugBank; DB00594; Amiloride.
DR DrugBank; DB00345; Aminohippuric acid.
DR DrugBank; DB00125; Arginine.
DR DrugBank; DB01053; Benzylpenicillin.
DR DrugBank; DB00122; Choline.
DR DrugBank; DB14006; Choline salicylate.
DR DrugBank; DB00501; Cimetidine.
DR DrugBank; DB00575; Clonidine.
DR DrugBank; DB00987; Cytarabine.
DR DrugBank; DB01151; Desipramine.
DR DrugBank; DB00983; Formoterol.
DR DrugBank; DB00536; Guanidine.
DR DrugBank; DB00458; Imipramine.
DR DrugBank; DB00332; Ipratropium.
DR DrugBank; DB00583; Levocarnitine.
DR DrugBank; DB01137; Levofloxacin.
DR DrugBank; DB00123; Lysine.
DR DrugBank; DB01043; Memantine.
DR DrugBank; DB06691; Mepyramine.
DR DrugBank; DB00184; Nicotine.
DR DrugBank; DB01165; Ofloxacin.
DR DrugBank; DB01035; Procainamide.
DR DrugBank; DB01917; Putrescine.
DR DrugBank; DB00908; Quinidine.
DR DrugBank; DB00468; Quinine.
DR DrugBank; DB14754; Solriamfetol.
DR DrugBank; DB03566; Spermidine.
DR DrugBank; DB00127; Spermine.
DR DrugBank; DB13943; Testosterone cypionate.
DR DrugBank; DB13944; Testosterone enanthate.
DR DrugBank; DB13946; Testosterone undecanoate.
DR DrugBank; DB08837; Tetraethylammonium.
DR DrugBank; DB01409; Tiotropium.
DR DrugBank; DB00661; Verapamil.
DR TCDB; 2.A.1.19.2; the major facilitator superfamily (mfs).
DR GlyGen; Q9H015; 3 sites.
DR iPTMnet; Q9H015; -.
DR PhosphoSitePlus; Q9H015; -.
DR BioMuta; SLC22A4; -.
DR DMDM; 146345508; -.
DR EPD; Q9H015; -.
DR jPOST; Q9H015; -.
DR MassIVE; Q9H015; -.
DR PaxDb; Q9H015; -.
DR PeptideAtlas; Q9H015; -.
DR PRIDE; Q9H015; -.
DR ProteomicsDB; 80197; -.
DR Antibodypedia; 26020; 143 antibodies from 25 providers.
DR DNASU; 6583; -.
DR Ensembl; ENST00000200652.4; ENSP00000200652.3; ENSG00000197208.6.
DR GeneID; 6583; -.
DR KEGG; hsa:6583; -.
DR MANE-Select; ENST00000200652.4; ENSP00000200652.3; NM_003059.3; NP_003050.2.
DR UCSC; uc003kwq.4; human.
DR CTD; 6583; -.
DR DisGeNET; 6583; -.
DR GeneCards; SLC22A4; -.
DR HGNC; HGNC:10968; SLC22A4.
DR HPA; ENSG00000197208; Tissue enhanced (bone).
DR MalaCards; SLC22A4; -.
DR MIM; 180300; phenotype.
DR MIM; 604190; gene.
DR neXtProt; NX_Q9H015; -.
DR OpenTargets; ENSG00000197208; -.
DR PharmGKB; PA332; -.
DR VEuPathDB; HostDB:ENSG00000197208; -.
DR eggNOG; KOG0255; Eukaryota.
DR GeneTree; ENSGT00940000154155; -.
DR HOGENOM; CLU_001265_33_4_1; -.
DR InParanoid; Q9H015; -.
DR OMA; AYFTAWL; -.
DR OrthoDB; 655566at2759; -.
DR PhylomeDB; Q9H015; -.
DR TreeFam; TF315847; -.
DR PathwayCommons; Q9H015; -.
DR Reactome; R-HSA-549127; Organic cation transport.
DR SignaLink; Q9H015; -.
DR BioGRID-ORCS; 6583; 9 hits in 1084 CRISPR screens.
DR GeneWiki; SLC22A4; -.
DR GenomeRNAi; 6583; -.
DR Pharos; Q9H015; Tbio.
DR PRO; PR:Q9H015; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q9H015; protein.
DR Bgee; ENSG00000197208; Expressed in bronchial epithelial cell and 121 other tissues.
DR Genevisible; Q9H015; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0015171; F:amino acid transmembrane transporter activity; IDA:ARUK-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0015226; F:carnitine transmembrane transporter activity; IDA:MGI.
DR GO; GO:0015491; F:cation:cation antiporter activity; IDA:BHF-UCL.
DR GO; GO:0000166; F:nucleotide binding; TAS:ProtInc.
DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL.
DR GO; GO:0015651; F:quaternary ammonium group transmembrane transporter activity; IDA:ARUK-UCL.
DR GO; GO:0008513; F:secondary active organic cation transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW.
DR GO; GO:0089718; P:amino acid import across plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0007589; P:body fluid secretion; TAS:ProtInc.
DR GO; GO:0009437; P:carnitine metabolic process; IEA:Ensembl.
DR GO; GO:0015879; P:carnitine transport; IDA:MGI.
DR GO; GO:0015695; P:organic cation transport; TAS:ProtInc.
DR GO; GO:0015697; P:quaternary ammonium group transport; IDA:ARUK-UCL.
DR GO; GO:0006814; P:sodium ion transport; IEA:UniProtKB-KW.
DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR GO; GO:0042908; P:xenobiotic transport; IDA:ARUK-UCL.
DR CDD; cd17376; MFS_SLC22A4_5_OCTN1_2; 1.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR005828; MFS_sugar_transport-like.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR004749; Orgcat_transp/SVOP.
DR InterPro; IPR045915; S22A4/5.
DR InterPro; IPR005829; Sugar_transporter_CS.
DR Pfam; PF00083; Sugar_tr; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR TIGRFAMs; TIGR00898; 2A0119; 1.
DR PROSITE; PS50850; MFS; 1.
DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Disease variant; Glycoprotein; Ion transport; Membrane;
KW Nucleotide-binding; Reference proteome; Sodium; Sodium transport; Symport;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..551
FT /note="Solute carrier family 22 member 4"
FT /id="PRO_0000220497"
FT TOPO_DOM 1..20
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 21..41
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 42..141
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 142..162
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 163..171
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 172..192
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 193..197
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 198..218
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 219..232
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 233..253
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 254..257
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 258..278
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 279..337
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 338..358
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 359..371
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 372..392
FT /note="Helical; Name=8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 393..399
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 400..420
FT /note="Helical; Name=9"
FT /evidence="ECO:0000255"
FT TOPO_DOM 421..426
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 427..447
FT /note="Helical; Name=10"
FT /evidence="ECO:0000255"
FT TOPO_DOM 448..460
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 461..481
FT /note="Helical; Name=11"
FT /evidence="ECO:0000255"
FT TOPO_DOM 482..486
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 487..507
FT /note="Helical; Name=12"
FT /evidence="ECO:0000255"
FT TOPO_DOM 508..551
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT BINDING 218..225
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255"
FT CARBOHYD 57
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 64
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 91
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 306
FT /note="I -> T (in dbSNP:rs272893)"
FT /evidence="ECO:0000269|PubMed:12436193,
FT ECO:0000269|PubMed:9426230"
FT /id="VAR_019528"
FT VARIANT 462
FT /note="G -> E (abrogates TEA transport activity;
FT dbSNP:rs4646201)"
FT /evidence="ECO:0000269|PubMed:12436193,
FT ECO:0000269|PubMed:15459889"
FT /id="VAR_019529"
FT VARIANT 503
FT /note="L -> F (reduces the ability to transport carnitine;
FT dbSNP:rs1050152)"
FT /evidence="ECO:0000269|PubMed:15107849,
FT ECO:0000269|PubMed:9426230"
FT /id="VAR_019530"
SQ SEQUENCE 551 AA; 62155 MW; C827A99AA78C9443 CRC64;
MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC RVPDAANLSS
AWRNNSVPLR LRDGREVPHS CSRYRLATIA NFSALGLEPG RDVDLGQLEQ ESCLDGWEFS
QDVYLSTVVT EWNLVCEDNW KVPLTTSLFF VGVLLGSFVS GQLSDRFGRK NVLFATMAVQ
TGFSFLQIFS ISWEMFTVLF VIVGMGQISN YVVAFILGTE ILGKSVRIIF STLGVCTFFA
VGYMLLPLFA YFIRDWRMLL LALTVPGVLC VPLWWFIPES PRWLISQRRF REAEDIIQKA
AKMNNIAVPA VIFDSVEELN PLKQQKAFIL DLFRTRNIAI MTIMSLLLWM LTSVGYFALS
LDAPNLHGDA YLNCFLSALI EIPAYITAWL LLRTLPRRYI IAAVLFWGGG VLLFIQLVPV
DYYFLSIGLV MLGKFGITSA FSMLYVFTAE LYPTLVRNMA VGVTSTASRV GSIIAPYFVY
LGAYNRMLPY IVMGSLTVLI GILTLFFPES LGMTLPETLE QMQKVKWFRS GKKTRDSMET
EENPKVLITA F
