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Q9H015

- S22A4_HUMAN

UniProt

Q9H015 - S22A4_HUMAN

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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

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. quaternary ammonium group transmembrane transporter activity Source: BHF-UCL
  7. secondary active organic cation transmembrane transporter activity Source: ProtInc
  8. 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. cation transmembrane transport Source: GOC
  6. organic cation transport Source: ProtInc
  7. quaternary ammonium group transport Source: BHF-UCL
  8. sodium ion transport Source: UniProtKB-KW
  9. transmembrane transport Source: Reactome
  10. triglyceride metabolic process Source: Ensembl
Complete GO annotation...

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
Complete GO annotation...

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.
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

BgeeiQ9H015.
CleanExiHS_SLC22A4.
ExpressionAtlasiQ9H015. baseline and differential.
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 119-510.
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.
GeneTreeiENSGT00760000118852.
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

« Hide

        10         20         30         40         50
MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC
60 70 80 90 100
RVPDAANLSS AWRNNSVPLR LRDGREVPHS CSRYRLATIA NFSALGLEPG
110 120 130 140 150
RDVDLGQLEQ ESCLDGWEFS QDVYLSTVVT EWNLVCEDNW KVPLTTSLFF
160 170 180 190 200
VGVLLGSFVS GQLSDRFGRK NVLFATMAVQ TGFSFLQIFS ISWEMFTVLF
210 220 230 240 250
VIVGMGQISN YVVAFILGTE ILGKSVRIIF STLGVCTFFA VGYMLLPLFA
260 270 280 290 300
YFIRDWRMLL LALTVPGVLC VPLWWFIPES PRWLISQRRF REAEDIIQKA
310 320 330 340 350
AKMNNIAVPA VIFDSVEELN PLKQQKAFIL DLFRTRNIAI MTIMSLLLWM
360 370 380 390 400
LTSVGYFALS LDAPNLHGDA YLNCFLSALI EIPAYITAWL LLRTLPRRYI
410 420 430 440 450
IAAVLFWGGG VLLFIQLVPV DYYFLSIGLV MLGKFGITSA FSMLYVFTAE
460 470 480 490 500
LYPTLVRNMA VGVTSTASRV GSIIAPYFVY LGAYNRMLPY IVMGSLTVLI
510 520 530 540 550
GILTLFFPES LGMTLPETLE QMQKVKWFRS GKKTRDSMET EENPKVLITA

F
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 119-510.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 112470. 1 interaction.
STRINGi 9606.ENSP00000200652.

Chemistry

ChEMBLi CHEMBL2073668.
DrugBanki DB00594. Amiloride.
DB00345. Aminohippurate.
DB01053. Benzylpenicillin.
DB00122. Choline.
DB00501. Cimetidine.
DB00575. Clonidine.
DB01151. Desipramine.
DB00536. Guanidine.
DB00458. Imipramine.
DB00332. Ipratropium bromide.
DB00125. L-Arginine.
DB00583. L-Carnitine.
DB00123. L-Lysine.
DB01137. Levofloxacin.
DB06691. Mepyramine.
DB00184. Nicotine.
DB01165. Ofloxacin.
DB01035. Procainamide.
DB00908. Quinidine.
DB00468. Quinine.
DB00127. Spermine.
DB00624. Testosterone.
DB01409. Tiotropium.
DB00661. Verapamil.

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.
PharmGKBi PA332.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0477.
GeneTreei ENSGT00760000118852.
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

Bgeei Q9H015.
CleanExi HS_SLC22A4.
ExpressionAtlasi Q9H015. baseline and differential.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 120 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