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Q9H015

- S22A4_HUMAN

UniProt

Q9H015 - S22A4_HUMAN

Protein

Solute carrier family 22 member 4

Gene

SLC22A4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 119 (01 Oct 2014)
      Sequence version 3 (01 May 2007)
      Previous versions | rss
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    Functioni

    Sodium-ion dependent, low affinity carnitine transporter. Probably transports one sodium ion with one molecule of carnitine. Also transports organic cations such as tetraethylammonium (TEA) without the involvement of sodium. Relative uptake activity ratio of carnitine to TEA is 1.78. A key substrate of this transporter seems to be ergothioneine (ET).2 Publications

    Kineticsi

    1. KM=0.470 mM for TEA (at 37 degrees Celsius and pH 7.4)2 Publications

    Vmax=0.974 nmol/min/mg enzyme toward TEA (at 37 degrees Celsius and pH 7.4)2 Publications

    pH dependencei

    More active at neutral and alkaline pHs than at acidic pHs.2 Publications

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi218 – 2258ATPSequence Analysis

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. carnitine transmembrane transporter activity Source: MGI
    3. cation:cation antiporter activity Source: BHF-UCL
    4. nucleotide binding Source: ProtInc
    5. PDZ domain binding Source: BHF-UCL
    6. protein binding Source: BHF-UCL
    7. quaternary ammonium group transmembrane transporter activity Source: BHF-UCL
    8. secondary active organic cation transmembrane transporter activity Source: ProtInc
    9. symporter activity Source: UniProtKB-KW

    GO - Biological processi

    1. body fluid secretion Source: ProtInc
    2. carnitine metabolic process Source: Ensembl
    3. carnitine transmembrane transport Source: GOC
    4. carnitine transport Source: MGI
    5. organic cation transport Source: ProtInc
    6. quaternary ammonium group transport Source: BHF-UCL
    7. sodium ion transport Source: UniProtKB-KW
    8. transmembrane transport Source: Reactome
    9. triglyceride metabolic process Source: Ensembl

    Keywords - Biological processi

    Ion transport, Sodium transport, Symport, Transport

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding, Sodium

    Enzyme and pathway databases

    ReactomeiREACT_22357. Organic cation transport.

    Protein family/group databases

    TCDBi2.A.1.19.2. the major facilitator superfamily (mfs).
    2.A.1.19.26. the major facilitator superfamily (mfs).

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Solute carrier family 22 member 4
    Alternative name(s):
    Ergothioneine transporter
    Short name:
    ET transporter
    Organic cation/carnitine transporter 1
    Gene namesi
    Name:SLC22A4
    Synonyms:ETT, OCTN1, UT2H
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 5

    Organism-specific databases

    HGNCiHGNC:10968. SLC22A4.

    Subcellular locationi

    GO - Cellular componenti

    1. apical plasma membrane Source: BHF-UCL
    2. integral component of plasma membrane Source: ProtInc
    3. mitochondrion Source: MGI
    4. plasma membrane Source: BHF-UCL

    Keywords - Cellular componenti

    Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures.1 Publication
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi180300. phenotype.
    Orphaneti206. Crohn disease.
    PharmGKBiPA332.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 551551Solute carrier family 22 member 4PRO_0000220497Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Glycosylationi57 – 571N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi64 – 641N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi91 – 911N-linked (GlcNAc...)Sequence Analysis

    Keywords - PTMi

    Glycoprotein

    Proteomic databases

    PaxDbiQ9H015.
    PRIDEiQ9H015.

    PTM databases

    PhosphoSiteiQ9H015.

    Expressioni

    Tissue specificityi

    Widely expressed. Highly expressed in whole blood, bone marrow, trachea and fetal liver. Weakly expressed in kidney, skeletal muscle, prostate, lung, pancreas, placenta, heart, uterus, spleen and spinal cord. Highly expressed in intestinal cell types affected by Crohn disease, including epithelial cells. Expressed in CD68 macrophage and CD43 T-cells but not in CD20 B-cells. Predominantly expressed in CD14 cells in peripheral blood mononuclear cells.3 Publications

    Inductioni

    Overexpressed upon TNF treatment.1 Publication

    Gene expression databases

    ArrayExpressiQ9H015.
    BgeeiQ9H015.
    CleanExiHS_SLC22A4.
    GenevestigatoriQ9H015.

    Organism-specific databases

    HPAiCAB015468.

    Interactioni

    Subunit structurei

    Interacts with PDZK1.By similarity

    Protein-protein interaction databases

    BioGridi112470. 1 interaction.
    STRINGi9606.ENSP00000200652.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9H015.
    SMRiQ9H015. Positions 150-311.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 2020CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini42 – 141100ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini163 – 1719CytoplasmicSequence Analysis
    Topological domaini193 – 1975ExtracellularSequence Analysis
    Topological domaini219 – 23214CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini254 – 2574ExtracellularSequence Analysis
    Topological domaini279 – 33759CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini359 – 37113ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini393 – 3997CytoplasmicSequence Analysis
    Topological domaini421 – 4266ExtracellularSequence Analysis
    Topological domaini448 – 46013CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini482 – 4865ExtracellularSequence Analysis
    Topological domaini508 – 55144CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei21 – 4121Helical; Name=1Sequence AnalysisAdd
    BLAST
    Transmembranei142 – 16221Helical; Name=2Sequence AnalysisAdd
    BLAST
    Transmembranei172 – 19221Helical; Name=3Sequence AnalysisAdd
    BLAST
    Transmembranei198 – 21821Helical; Name=4Sequence AnalysisAdd
    BLAST
    Transmembranei233 – 25321Helical; Name=5Sequence AnalysisAdd
    BLAST
    Transmembranei258 – 27821Helical; Name=6Sequence AnalysisAdd
    BLAST
    Transmembranei338 – 35821Helical; Name=7Sequence AnalysisAdd
    BLAST
    Transmembranei372 – 39221Helical; Name=8Sequence AnalysisAdd
    BLAST
    Transmembranei400 – 42021Helical; Name=9Sequence AnalysisAdd
    BLAST
    Transmembranei427 – 44721Helical; Name=10Sequence AnalysisAdd
    BLAST
    Transmembranei461 – 48121Helical; Name=11Sequence AnalysisAdd
    BLAST
    Transmembranei487 – 50721Helical; Name=12Sequence AnalysisAdd
    BLAST

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiCOG0477.
    HOGENOMiHOG000234570.
    HOVERGENiHBG061545.
    InParanoidiQ9H015.
    KOiK08202.
    OMAiNIAVPAV.
    OrthoDBiEOG7C8GH9.
    PhylomeDBiQ9H015.
    TreeFamiTF315847.

    Family and domain databases

    InterProiIPR020846. MFS_dom.
    IPR016196. MFS_dom_general_subst_transpt.
    IPR004749. Orgcat_transp.
    IPR005828. Sub_transporter.
    IPR005829. Sugar_transporter_CS.
    [Graphical view]
    PfamiPF00083. Sugar_tr. 1 hit.
    [Graphical view]
    SUPFAMiSSF103473. SSF103473. 1 hit.
    TIGRFAMsiTIGR00898. 2A0119. 1 hit.
    PROSITEiPS50850. MFS. 1 hit.
    PS00216. SUGAR_TRANSPORT_1. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q9H015-1 [UniParc]FASTAAdd to Basket

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    MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC    50
    RVPDAANLSS AWRNNSVPLR LRDGREVPHS CSRYRLATIA NFSALGLEPG 100
    RDVDLGQLEQ ESCLDGWEFS QDVYLSTVVT EWNLVCEDNW KVPLTTSLFF 150
    VGVLLGSFVS GQLSDRFGRK NVLFATMAVQ TGFSFLQIFS ISWEMFTVLF 200
    VIVGMGQISN YVVAFILGTE ILGKSVRIIF STLGVCTFFA VGYMLLPLFA 250
    YFIRDWRMLL LALTVPGVLC VPLWWFIPES PRWLISQRRF REAEDIIQKA 300
    AKMNNIAVPA VIFDSVEELN PLKQQKAFIL DLFRTRNIAI MTIMSLLLWM 350
    LTSVGYFALS LDAPNLHGDA YLNCFLSALI EIPAYITAWL LLRTLPRRYI 400
    IAAVLFWGGG VLLFIQLVPV DYYFLSIGLV MLGKFGITSA FSMLYVFTAE 450
    LYPTLVRNMA VGVTSTASRV GSIIAPYFVY LGAYNRMLPY IVMGSLTVLI 500
    GILTLFFPES LGMTLPETLE QMQKVKWFRS GKKTRDSMET EENPKVLITA 550
    F 551
    Length:551
    Mass (Da):62,155
    Last modified:May 1, 2007 - v3
    Checksum:iC827A99AA78C9443
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti306 – 3061I → T.2 Publications
    Corresponds to variant rs272893 [ dbSNP | Ensembl ].
    VAR_019528
    Natural varianti462 – 4621G → E Abrogates TEA transport activity. 1 Publication
    Corresponds to variant rs4646201 [ dbSNP | Ensembl ].
    VAR_019529
    Natural varianti503 – 5031L → F Reduces the ability to transport carnitine. 2 Publications
    Corresponds to variant rs1050152 [ dbSNP | Ensembl ].
    VAR_019530

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB007448 mRNA. Translation: BAA23356.1.
    Y09881 mRNA. Translation: CAA71007.1.
    AC008599 Genomic DNA. No translation available.
    AC034220 Genomic DNA. No translation available.
    BC028313 mRNA. Translation: AAH28313.1.
    CCDSiCCDS4153.1.
    RefSeqiNP_003050.2. NM_003059.2.
    UniGeneiHs.310591.

    Genome annotation databases

    EnsembliENST00000200652; ENSP00000200652; ENSG00000197208.
    GeneIDi6583.
    KEGGihsa:6583.
    UCSCiuc003kwq.3. human.

    Polymorphism databases

    DMDMi146345508.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB007448 mRNA. Translation: BAA23356.1 .
    Y09881 mRNA. Translation: CAA71007.1 .
    AC008599 Genomic DNA. No translation available.
    AC034220 Genomic DNA. No translation available.
    BC028313 mRNA. Translation: AAH28313.1 .
    CCDSi CCDS4153.1.
    RefSeqi NP_003050.2. NM_003059.2.
    UniGenei Hs.310591.

    3D structure databases

    ProteinModelPortali Q9H015.
    SMRi Q9H015. Positions 150-311.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 112470. 1 interaction.
    STRINGi 9606.ENSP00000200652.

    Chemistry

    ChEMBLi CHEMBL2073668.
    DrugBanki DB00583. L-Carnitine.

    Protein family/group databases

    TCDBi 2.A.1.19.2. the major facilitator superfamily (mfs).
    2.A.1.19.26. the major facilitator superfamily (mfs).

    PTM databases

    PhosphoSitei Q9H015.

    Polymorphism databases

    DMDMi 146345508.

    Proteomic databases

    PaxDbi Q9H015.
    PRIDEi Q9H015.

    Protocols and materials databases

    DNASUi 6583.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000200652 ; ENSP00000200652 ; ENSG00000197208 .
    GeneIDi 6583.
    KEGGi hsa:6583.
    UCSCi uc003kwq.3. human.

    Organism-specific databases

    CTDi 6583.
    GeneCardsi GC05P131658.
    H-InvDB HIX0024844.
    HGNCi HGNC:10968. SLC22A4.
    HPAi CAB015468.
    MIMi 180300. phenotype.
    604190. gene.
    neXtProti NX_Q9H015.
    Orphaneti 206. Crohn disease.
    PharmGKBi PA332.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0477.
    HOGENOMi HOG000234570.
    HOVERGENi HBG061545.
    InParanoidi Q9H015.
    KOi K08202.
    OMAi NIAVPAV.
    OrthoDBi EOG7C8GH9.
    PhylomeDBi Q9H015.
    TreeFami TF315847.

    Enzyme and pathway databases

    Reactomei REACT_22357. Organic cation transport.

    Miscellaneous databases

    GeneWikii SLC22A4.
    GenomeRNAii 6583.
    NextBioi 25617.
    PROi Q9H015.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q9H015.
    Bgeei Q9H015.
    CleanExi HS_SLC22A4.
    Genevestigatori Q9H015.

    Family and domain databases

    InterProi IPR020846. MFS_dom.
    IPR016196. MFS_dom_general_subst_transpt.
    IPR004749. Orgcat_transp.
    IPR005828. Sub_transporter.
    IPR005829. Sugar_transporter_CS.
    [Graphical view ]
    Pfami PF00083. Sugar_tr. 1 hit.
    [Graphical view ]
    SUPFAMi SSF103473. SSF103473. 1 hit.
    TIGRFAMsi TIGR00898. 2A0119. 1 hit.
    PROSITEi PS50850. MFS. 1 hit.
    PS00216. SUGAR_TRANSPORT_1. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1."
      Tamai I., Yabuuchi H., Nezu J., Sai Y., Oku A., Shimane M., Tsuji A.
      FEBS Lett. 419:107-111(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES, VARIANTS THR-306 AND PHE-503.
      Tissue: Fetal liver.
    2. Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
    3. "The DNA sequence and comparative analysis of human chromosome 5."
      Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.
      , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
      Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Colon.
    5. "Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations."
      Yabuuchi H., Tamai I., Nezu J., Sakamoto K., Oku A., Shimane M., Sai Y., Tsuji A.
      J. Pharmacol. Exp. Ther. 289:768-773(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    6. "An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis."
      Tokuhiro S., Yamada R., Chang X., Suzuki A., Kochi Y., Sawada T., Suzuki M., Nagasaki M., Ohtsuki M., Ono M., Furukawa H., Nagashima M., Yoshino S., Mabuchi A., Sekine A., Saito S., Takahashi A., Tsunoda T., Nakamura Y., Yamamoto K.
      Nat. Genet. 35:341-348(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION, TISSUE SPECIFICITY, INVOLVEMENT IN RA.
    7. "Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population."
      Saito S., Iida A., Sekine A., Ogawa C., Kawauchi S., Higuchi S., Nakamura Y.
      J. Hum. Genet. 47:576-584(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS THR-306 AND GLU-462.
    8. "Functional characterization of human organic cation transporter OCTN1 single nucleotide polymorphisms in the Japanese population."
      Kawasaki Y., Kato Y., Sai Y., Tsuji A.
      J. Pharm. Sci. 93:2920-2926(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANT GLU-462, BIOPHYSICOCHEMICAL PROPERTIES.
    9. Cited for: VARIANT PHE-503, TISSUE SPECIFICITY.

    Entry informationi

    Entry nameiS22A4_HUMAN
    AccessioniPrimary (citable) accession number: Q9H015
    Secondary accession number(s): O14546
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 19, 2004
    Last sequence update: May 1, 2007
    Last modified: October 1, 2014
    This is version 119 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Caution

    PubMed:9426230 reported that this protein does not transport carnitine, however, experiments were done with the Phe-503 variant, which affects the ability to transport carnitine. PubMed:15459889 showed that, although weakly, it can also transport carnitine at some level. Its function in carnitine transport is therefore unclear.Curated

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 5
      Human chromosome 5: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3