ID   S22A4_MOUSE             Reviewed;         553 AA.
AC   Q9Z306;
DT   19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   27-MAR-2024, entry version 167.
DE   RecName: Full=Solute carrier family 22 member 4 {ECO:0000303|PubMed:15489334};
DE   AltName: Full=Organic cation/carnitine transporter 1 {ECO:0000303|PubMed:11010964};
DE            Short=Octn1 {ECO:0000303|PubMed:11010964};
GN   Name=Slc22a4 {ECO:0000312|MGI:MGI:1353479}; Synonyms=Octn1;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, TISSUE
RP   SPECIFICITY, AND MISCELLANEOUS.
RC   STRAIN=C57BL/6J; TISSUE=Kidney;
RX   PubMed=11010964; DOI=10.1074/jbc.m005340200;
RA   Tamai I., Ohashi R., Nezu J., Sai Y., Kobayashi D., Oku A., Shimane M.,
RA   Tsuji A.;
RT   "Molecular and functional characterization of organic cation/carnitine
RT   transporter family in mice.";
RL   J. Biol. Chem. 275:40064-40072(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Mammary tumor;
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   INTERACTION WITH PDZK1.
RX   PubMed=14531806; DOI=10.1046/j.1523-1755.2003.00266.x;
RA   Gisler S.M., Pribanic S., Bacic D., Forrer P., Gantenbein A.,
RA   Sabourin L.A., Tsuji A., Zhao Z.-S., Manser E., Biber J., Murer H.;
RT   "PDZK1: I. a major scaffolder in brush borders of proximal tubular cells.";
RL   Kidney Int. 64:1733-1745(2003).
RN   [4]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MISCELLANEOUS.
RX   PubMed=15832501; DOI=10.1021/mp0340082;
RA   Tamai I., Nakanishi T., Kobayashi D., China K., Kosugi Y., Nezu J., Sai Y.,
RA   Tsuji A.;
RT   "Involvement of OCTN1 (SLC22A4) in pH-dependent transport of organic
RT   cations.";
RL   Mol. Pharm. 1:57-66(2004).
RN   [5]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=16729965; DOI=10.1016/j.bbrc.2006.05.026;
RA   Lamhonwah A.M., Tein I.;
RT   "Novel localization of OCTN1, an organic cation/carnitine transporter, to
RT   mammalian mitochondria.";
RL   Biochem. Biophys. Res. Commun. 345:1315-1325(2006).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Kidney;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [7]
RP   FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP   AND DISRUPTION PHENOTYPE.
RX   PubMed=20601551; DOI=10.1124/dmd.110.032763;
RA   Sugiura T., Kato S., Shimizu T., Wakayama T., Nakamichi N., Kubo Y.,
RA   Iwata D., Suzuki K., Soga T., Asano M., Iseki S., Tamai I., Tsuji A.,
RA   Kato Y.;
RT   "Functional expression of carnitine/organic cation transporter
RT   OCTN1/SLC22A4 in mouse small intestine and liver.";
RL   Drug Metab. Dispos. 38:1665-1672(2010).
RN   [8]
RP   FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP   DISRUPTION PHENOTYPE.
RX   PubMed=20224991; DOI=10.1007/s11095-010-0076-z;
RA   Kato Y., Kubo Y., Iwata D., Kato S., Sudo T., Sugiura T., Kagaya T.,
RA   Wakayama T., Hirayama A., Sugimoto M., Sugihara K., Kaneko S., Soga T.,
RA   Asano M., Tomita M., Matsui T., Wada M., Tsuji A.;
RT   "Gene knockout and metabolome analysis of carnitine/organic cation
RT   transporter OCTN1.";
RL   Pharm. Res. 27:832-840(2010).
CC   -!- FUNCTION: Transporter that mediates the transport of endogenous and
CC       microbial zwitterions and organic cations (PubMed:11010964,
CC       PubMed:20601551, PubMed:20224991). Functions as a Na(+)-dependent and
CC       pH-dependent high affinity microbial symporter of potent food-derived
CC       antioxidant ergothioeine (By similarity). Transports one sodium ion
CC       with one ergothioeine molecule (By similarity). Involved in the
CC       absorption of ergothioneine from the luminal/apical side of the small
CC       intestine and renal tubular cells, and into non-parenchymal liver
CC       cells, thereby contributing to maintain steady-state ergothioneine
CC       level in the body (PubMed:20601551, PubMed:20224991). Also mediates the
CC       bidirectional transport of acetycholine, although the exact transport
CC       mechanism has not been fully identified yet (By similarity). Most
CC       likely exports anti-inflammatory acetylcholine in non-neuronal tissues,
CC       thereby contributing to the non-neuronal cholinergic system (By
CC       similarity). Displays a general physiological role linked to better
CC       survival by controlling inflammation and oxidative stress, which may be
CC       related to ergothioneine and acetycholine transports (PubMed:20224991).
CC       May also function as a low-affinity Na(+)-dependent transporter of L-
CC       carnitine through the mitochondrial membrane, thereby maintaining
CC       intracellular carnitine homeostasis (PubMed:11010964, PubMed:16729965).
CC       May contribute to regulate the transport of cationic compounds in
CC       testis across the blood-testis-barrier (By similarity).
CC       {ECO:0000250|UniProtKB:Q9H015, ECO:0000250|UniProtKB:Q9R141,
CC       ECO:0000269|PubMed:11010964, ECO:0000269|PubMed:16729965,
CC       ECO:0000269|PubMed:20224991, ECO:0000269|PubMed:20601551}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ergothioneine(out) + Na(+)(out) = ergothioneine(in) +
CC         Na(+)(in); Xref=Rhea:RHEA:75843, ChEBI:CHEBI:29101,
CC         ChEBI:CHEBI:134344; Evidence={ECO:0000269|PubMed:20224991,
CC         ECO:0000269|PubMed:20601551};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=acetylcholine(in) = acetylcholine(out); Xref=Rhea:RHEA:74663,
CC         ChEBI:CHEBI:15355; Evidence={ECO:0000250|UniProtKB:Q9H015};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(R)-carnitine(out) + Na(+)(out) = (R)-carnitine(in) +
CC         Na(+)(in); Xref=Rhea:RHEA:72091, ChEBI:CHEBI:16347,
CC         ChEBI:CHEBI:29101; Evidence={ECO:0000305|PubMed:11010964};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=glycine betaine(out) + Na(+)(out) = glycine betaine(in) +
CC         Na(+)(in); Xref=Rhea:RHEA:72115, ChEBI:CHEBI:17750,
CC         ChEBI:CHEBI:29101; Evidence={ECO:0000250|UniProtKB:Q9H015};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:72116;
CC         Evidence={ECO:0000250|UniProtKB:Q9H015};
CC   -!- ACTIVITY REGULATION: Allosterically activated by intracellular ATP.
CC       {ECO:0000250|UniProtKB:Q9H015}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=4.68 uM for ergothioneine (at pH 7.4)
CC         {ECO:0000269|PubMed:20224991};
CC         Vmax=531 pmol/min/mg enzyme for ergothioneine uptake (at pH 7.4)
CC         {ECO:0000269|PubMed:20224991};
CC   -!- SUBUNIT: Interacts with PDZK1. {ECO:0000269|PubMed:14531806}.
CC   -!- SUBCELLULAR LOCATION: Apical cell membrane
CC       {ECO:0000269|PubMed:15832501, ECO:0000269|PubMed:20601551}; Multi-pass
CC       membrane protein {ECO:0000305}. Mitochondrion membrane
CC       {ECO:0000269|PubMed:16729965}; Multi-pass membrane protein
CC       {ECO:0000305}. Basal cell membrane {ECO:0000250|UniProtKB:Q9H015};
CC       Multi-pass membrane protein {ECO:0000305}. Note=Localized to the apical
CC       membrane of small intestines (PubMed:20601551). Localized to the apical
CC       membrane of cortical proximal tubular epithelial cells in kidney
CC       (PubMed:15832501). {ECO:0000269|PubMed:15832501,
CC       ECO:0000269|PubMed:20601551}.
CC   -!- TISSUE SPECIFICITY: Expressed in kidney (PubMed:11010964,
CC       PubMed:15832501). Expressed in small intestines (PubMed:20601551).
CC       Expressed in liver in non-parenchymal liver tissue such as sinusoidal
CC       vessels (PubMed:11010964, PubMed:20601551). Weakly expressed in lung
CC       and brain (PubMed:11010964). Expressed in testis and spleen
CC       (PubMed:11010964). Expressed in heart (PubMed:16729965).
CC       {ECO:0000269|PubMed:11010964, ECO:0000269|PubMed:15832501,
CC       ECO:0000269|PubMed:16729965, ECO:0000269|PubMed:20601551}.
CC   -!- DISRUPTION PHENOTYPE: Knockout mice developed normally and did not
CC       display any gross phenotypic abnormalities. Knockout mice show a
CC       complete deficiency of ergothioneine in heart, liver, small intestine,
CC       kidney and erythrocytes. Impaired intestinal absorption and renal
CC       reabsorption of ergothioneine (PubMed:20224991, PubMed:20601551). Lower
CC       tolerance to intestinal oxidative stress (PubMed:20224991).
CC       {ECO:0000269|PubMed:20224991, ECO:0000269|PubMed:20601551}.
CC   -!- MISCELLANEOUS: Mediates the Na(+)-independent and pH-dependent
CC       bidirectional transport of exogenous prototype organic cation
CC       tetraethylammonium (TEA). {ECO:0000269|PubMed:11010964,
CC       ECO:0000269|PubMed:15832501}.
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: It is unclear whether it transports carnitine in vivo.
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; AB016257; BAA36626.1; -; mRNA.
DR   EMBL; BC010590; AAH10590.1; -; mRNA.
DR   CCDS; CCDS24689.1; -.
DR   RefSeq; NP_062661.1; NM_019687.4.
DR   AlphaFoldDB; Q9Z306; -.
DR   SMR; Q9Z306; -.
DR   STRING; 10090.ENSMUSP00000020586; -.
DR   ChEMBL; CHEMBL2073694; -.
DR   GlyCosmos; Q9Z306; 3 sites, No reported glycans.
DR   GlyGen; Q9Z306; 3 sites.
DR   iPTMnet; Q9Z306; -.
DR   PhosphoSitePlus; Q9Z306; -.
DR   SwissPalm; Q9Z306; -.
DR   jPOST; Q9Z306; -.
DR   PaxDb; 10090-ENSMUSP00000020586; -.
DR   ProteomicsDB; 253357; -.
DR   Antibodypedia; 26020; 179 antibodies from 25 providers.
DR   DNASU; 30805; -.
DR   Ensembl; ENSMUST00000020586.7; ENSMUSP00000020586.7; ENSMUSG00000020334.7.
DR   GeneID; 30805; -.
DR   KEGG; mmu:30805; -.
DR   UCSC; uc007ixe.1; mouse.
DR   AGR; MGI:1353479; -.
DR   CTD; 6583; -.
DR   MGI; MGI:1353479; Slc22a4.
DR   VEuPathDB; HostDB:ENSMUSG00000020334; -.
DR   eggNOG; KOG0255; Eukaryota.
DR   GeneTree; ENSGT00940000154155; -.
DR   HOGENOM; CLU_001265_33_4_1; -.
DR   InParanoid; Q9Z306; -.
DR   OMA; WTSIPTI; -.
DR   OrthoDB; 1448128at2759; -.
DR   PhylomeDB; Q9Z306; -.
DR   TreeFam; TF315847; -.
DR   Reactome; R-MMU-549127; Organic cation transport.
DR   BioGRID-ORCS; 30805; 4 hits in 79 CRISPR screens.
DR   ChiTaRS; Slc22a4; mouse.
DR   PRO; PR:Q9Z306; -.
DR   Proteomes; UP000000589; Chromosome 11.
DR   RNAct; Q9Z306; Protein.
DR   Bgee; ENSMUSG00000020334; Expressed in right kidney and 120 other cell types or tissues.
DR   GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR   GO; GO:0009925; C:basal plasma membrane; ISS:UniProtKB.
DR   GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:MGI.
DR   GO; GO:0005277; F:acetylcholine transmembrane transporter activity; ISO:MGI.
DR   GO; GO:0015171; F:amino acid transmembrane transporter activity; ISO:MGI.
DR   GO; GO:0015199; F:amino-acid betaine transmembrane transporter activity; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0015226; F:carnitine transmembrane transporter activity; IDA:MGI.
DR   GO; GO:0015101; F:organic cation transmembrane transporter activity; ISO:MGI.
DR   GO; GO:0030165; F:PDZ domain binding; ISO:MGI.
DR   GO; GO:0015651; F:quaternary ammonium group transmembrane transporter activity; ISO:MGI.
DR   GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW.
DR   GO; GO:0089718; P:amino acid import across plasma membrane; ISO:MGI.
DR   GO; GO:0009437; P:carnitine metabolic process; IGI:MGI.
DR   GO; GO:0015879; P:carnitine transport; IDA:MGI.
DR   GO; GO:0015697; P:quaternary ammonium group transport; IDA:MGI.
DR   GO; GO:0006814; P:sodium ion transport; IEA:UniProtKB-KW.
DR   GO; GO:0006641; P:triglyceride metabolic process; IGI:MGI.
DR   GO; GO:0042908; P:xenobiotic transport; ISO:MGI.
DR   Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 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; IPR005829; Sugar_transporter_CS.
DR   NCBIfam; TIGR00898; 2A0119; 1.
DR   PANTHER; PTHR24064; SOLUTE CARRIER FAMILY 22 MEMBER; 1.
DR   PANTHER; PTHR24064:SF222; SOLUTE CARRIER FAMILY 22 MEMBER 4; 1.
DR   Pfam; PF00083; Sugar_tr; 1.
DR   SUPFAM; SSF103473; MFS general substrate transporter; 1.
DR   PROSITE; PS50850; MFS; 1.
DR   PROSITE; PS00216; SUGAR_TRANSPORT_1; 1.
DR   Genevisible; Q9Z306; MM.
PE   1: Evidence at protein level;
KW   ATP-binding; Cell membrane; Glycoprotein; Ion transport; Membrane;
KW   Mitochondrion; Nucleotide-binding; Reference proteome; Sodium;
KW   Sodium transport; Symport; Transmembrane; Transmembrane helix; Transport.
FT   CHAIN           1..553
FT                   /note="Solute carrier family 22 member 4"
FT                   /id="PRO_0000220498"
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..142
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        143..163
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        164..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..339
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        340..360
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        361..373
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        374..394
FT                   /note="Helical; Name=8"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        395..400
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        401..421
FT                   /note="Helical; Name=9"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        422..428
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        429..449
FT                   /note="Helical; Name=10"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        450..462
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        463..483
FT                   /note="Helical; Name=11"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        484..488
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        489..509
FT                   /note="Helical; Name=12"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        510..553
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"
SQ   SEQUENCE   553 AA;  62290 MW;  C4D66BC061398653 CRC64;
     MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC LVPDTVNLSS
     SWRNHSIPLE TKDGRQVPQS CRRYRLATIA NFSAMGLEPG QDVDLEQLEQ ESCLDGWEYD
     KDIFLSTIVT EWNLVCEDDW KTPLTTSLFF VGVLCGSFVS GQLSDRFGRK KVLFATMAVQ
     TGFSFVQIFS TNWEMFTVLF AIVGMGQISN YVVAFILGTE ILSKSVRIIF STLGVCTFFA
     IGYMVLPLFA YFIRDWRMLL LALTLPGLFC VPLWWFIPES PRWLISQRRF AEAEQIIQKA
     AKMNSIVAPA GIFDPLELQE LNSLKQQKVI ILDLFRTRNI ATITVMAVML WMLTSVGYFA
     LSLNVPNLHG DVYLNCFLSG LIEVPAYFTA WLLLRTLPRR YIIAGVLFWG GGVLLLIQVV
     PEDYNFVSIG LVMLGKFGIT SAFSMLYVFT AELYPTLVRN MAVGITSMAS RVGSIIAPYF
     VYLGAYNRLL PYILMGSLTV LIGIITLFFP ESFGVTLPEN LEQMQKVRGF RCGKKSTVSV
     DREESPKVLI TAF
//