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Q9H015 (S22A4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Solute carrier family 22 member 4
Alternative name(s):
Ergothioneine transporter
Short name=ET transporter
Organic cation/carnitine transporter 1
Gene names
Name:SLC22A4
Synonyms:ETT, OCTN1, UT2H
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length551 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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). Ref.2 Ref.5

Subunit structure

Interacts with PDZK1 By similarity.

Subcellular location

Membrane; Multi-pass membrane protein.

Tissue specificity

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. Ref.1 Ref.6 Ref.9

Induction

Overexpressed upon TNF treatment. Ref.6

Involvement in disease

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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.6

Sequence similarities

Belongs to the major facilitator (TC 2.A.1) superfamily. Organic cation transporter (TC 2.A.1.19) family. [View classification]

Caution

Ref.1 reported that this protein does not transport carnitine, however, experiments were done with the Phe-503 variant, which affects the ability to transport carnitine. Ref.8 showed that, although weakly, it can also transport carnitine at some level. Its function in carnitine transport is therefore unclear.

Biophysicochemical properties

Kinetic parameters:

KM=0.470 mM for TEA (at 37 degrees Celsius and pH 7.4) Ref.1 Ref.8

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

pH dependence:

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

Ontologies

Keywords
   Biological processIon transport
Sodium transport
Symport
Transport
   Cellular componentMembrane
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainTransmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
Sodium
   PTMGlycoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processbody fluid secretion

Traceable author statement Ref.1. Source: ProtInc

carnitine metabolic process

Inferred from electronic annotation. Source: Ensembl

carnitine transmembrane transport

Inferred from direct assay PubMed 16729965. Source: GOC

carnitine transport

Inferred from direct assay PubMed 16729965. Source: MGI

organic cation transport

Traceable author statement Ref.1. Source: ProtInc

quaternary ammonium group transport

Inferred from direct assay Ref.1. Source: BHF-UCL

sodium ion transport

Inferred from electronic annotation. Source: UniProtKB-KW

transmembrane transport

Traceable author statement. Source: Reactome

triglyceride metabolic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentapical plasma membrane

Inferred from direct assay PubMed 18641280. Source: BHF-UCL

integral component of plasma membrane

Traceable author statement Ref.1. Source: ProtInc

mitochondrion

Inferred from direct assay PubMed 16729965. Source: MGI

plasma membrane

Inferred by curator Ref.1. Source: BHF-UCL

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

PDZ domain binding

Inferred from physical interaction PubMed 15523054. Source: BHF-UCL

carnitine transmembrane transporter activity

Inferred from direct assay PubMed 16729965. Source: MGI

cation:cation antiporter activity

Inferred from direct assay Ref.1. Source: BHF-UCL

nucleotide binding

Traceable author statement Ref.1. Source: ProtInc

protein binding

Inferred from physical interaction PubMed 15523054. Source: BHF-UCL

quaternary ammonium group transmembrane transporter activity

Inferred from direct assay Ref.1. Source: BHF-UCL

secondary active organic cation transmembrane transporter activity

Traceable author statement Ref.1. Source: ProtInc

symporter activity

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 551551Solute carrier family 22 member 4
PRO_0000220497

Regions

Topological domain1 – 2020Cytoplasmic Potential
Transmembrane21 – 4121Helical; Name=1; Potential
Topological domain42 – 141100Extracellular Potential
Transmembrane142 – 16221Helical; Name=2; Potential
Topological domain163 – 1719Cytoplasmic Potential
Transmembrane172 – 19221Helical; Name=3; Potential
Topological domain193 – 1975Extracellular Potential
Transmembrane198 – 21821Helical; Name=4; Potential
Topological domain219 – 23214Cytoplasmic Potential
Transmembrane233 – 25321Helical; Name=5; Potential
Topological domain254 – 2574Extracellular Potential
Transmembrane258 – 27821Helical; Name=6; Potential
Topological domain279 – 33759Cytoplasmic Potential
Transmembrane338 – 35821Helical; Name=7; Potential
Topological domain359 – 37113Extracellular Potential
Transmembrane372 – 39221Helical; Name=8; Potential
Topological domain393 – 3997Cytoplasmic Potential
Transmembrane400 – 42021Helical; Name=9; Potential
Topological domain421 – 4266Extracellular Potential
Transmembrane427 – 44721Helical; Name=10; Potential
Topological domain448 – 46013Cytoplasmic Potential
Transmembrane461 – 48121Helical; Name=11; Potential
Topological domain482 – 4865Extracellular Potential
Transmembrane487 – 50721Helical; Name=12; Potential
Topological domain508 – 55144Cytoplasmic Potential
Nucleotide binding218 – 2258ATP Potential

Amino acid modifications

Glycosylation571N-linked (GlcNAc...) Potential
Glycosylation641N-linked (GlcNAc...) Potential
Glycosylation911N-linked (GlcNAc...) Potential

Natural variations

Natural variant3061I → T. Ref.1 Ref.7
Corresponds to variant rs272893 [ dbSNP | Ensembl ].
VAR_019528
Natural variant4621G → E Abrogates TEA transport activity. Ref.7 Ref.8
Corresponds to variant rs4646201 [ dbSNP | Ensembl ].
VAR_019529
Natural variant5031L → F Reduces the ability to transport carnitine. Ref.1 Ref.9
Corresponds to variant rs1050152 [ dbSNP | Ensembl ].
VAR_019530

Sequences

Sequence LengthMass (Da)Tools
Q9H015 [UniParc].

Last modified May 1, 2007. Version 3.
Checksum: C827A99AA78C9443

FASTA55162,155
        10         20         30         40         50         60 
MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC RVPDAANLSS 

        70         80         90        100        110        120 
AWRNNSVPLR LRDGREVPHS CSRYRLATIA NFSALGLEPG RDVDLGQLEQ ESCLDGWEFS 

       130        140        150        160        170        180 
QDVYLSTVVT EWNLVCEDNW KVPLTTSLFF VGVLLGSFVS GQLSDRFGRK NVLFATMAVQ 

       190        200        210        220        230        240 
TGFSFLQIFS ISWEMFTVLF VIVGMGQISN YVVAFILGTE ILGKSVRIIF STLGVCTFFA 

       250        260        270        280        290        300 
VGYMLLPLFA YFIRDWRMLL LALTVPGVLC VPLWWFIPES PRWLISQRRF REAEDIIQKA 

       310        320        330        340        350        360 
AKMNNIAVPA VIFDSVEELN PLKQQKAFIL DLFRTRNIAI MTIMSLLLWM LTSVGYFALS 

       370        380        390        400        410        420 
LDAPNLHGDA YLNCFLSALI EIPAYITAWL LLRTLPRRYI IAAVLFWGGG VLLFIQLVPV 

       430        440        450        460        470        480 
DYYFLSIGLV MLGKFGITSA FSMLYVFTAE LYPTLVRNMA VGVTSTASRV GSIIAPYFVY 

       490        500        510        520        530        540 
LGAYNRMLPY IVMGSLTVLI GILTLFFPES LGMTLPETLE QMQKVKWFRS GKKTRDSMET 

       550 
EENPKVLITA F 

« Hide

References

« Hide 'large scale' references
[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]"Discovery of the ergothioneine transporter."
Gruendemann D., Harlfinger S., Golz S., Geerts A., Lazar A., Berkels R., Jung N., Rubbert A., Schoemig E.
Proc. Natl. Acad. Sci. U.S.A. 102:5256-5261(2005) [PubMed] [Europe PMC] [Abstract]
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. expand/collapse author list , 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]"Functional variants of OCTN cation transporter genes are associated with Crohn disease."
Peltekova V.D., Wintle R.F., Rubin L.A., Amos C.I., Huang Q., Gu X., Newman B., Van Oene M., Cescon D., Greenberg G., Griffiths A.M., St George-Hyslop P.H., Siminovitch K.A.
Nat. Genet. 36:471-475(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT PHE-503, TISSUE SPECIFICITY.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS4153.1.
RefSeqNP_003050.2. NM_003059.2.
UniGeneHs.310591.

3D structure databases

ProteinModelPortalQ9H015.
SMRQ9H015. Positions 150-311.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112470. 1 interaction.
STRING9606.ENSP00000200652.

Chemistry

ChEMBLCHEMBL2073668.
DrugBankDB00583. L-Carnitine.

Protein family/group databases

TCDB2.A.1.19.2. the major facilitator superfamily (mfs).
2.A.1.19.26. the major facilitator superfamily (mfs).

PTM databases

PhosphoSiteQ9H015.

Polymorphism databases

DMDM146345508.

Proteomic databases

PaxDbQ9H015.
PRIDEQ9H015.

Protocols and materials databases

DNASU6583.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000200652; ENSP00000200652; ENSG00000197208.
GeneID6583.
KEGGhsa:6583.
UCSCuc003kwq.3. human.

Organism-specific databases

CTD6583.
GeneCardsGC05P131658.
H-InvDBHIX0024844.
HGNCHGNC:10968. SLC22A4.
HPACAB015468.
MIM180300. phenotype.
604190. gene.
neXtProtNX_Q9H015.
Orphanet206. Crohn disease.
PharmGKBPA332.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0477.
HOGENOMHOG000234570.
HOVERGENHBG061545.
InParanoidQ9H015.
KOK08202.
OMANIAVPAV.
OrthoDBEOG7C8GH9.
PhylomeDBQ9H015.
TreeFamTF315847.

Enzyme and pathway databases

ReactomeREACT_15518. Transmembrane transport of small molecules.

Gene expression databases

ArrayExpressQ9H015.
BgeeQ9H015.
CleanExHS_SLC22A4.
GenevestigatorQ9H015.

Family and domain databases

InterProIPR020846. MFS_dom.
IPR016196. MFS_dom_general_subst_transpt.
IPR004749. Orgcat_transp.
IPR005828. Sub_transporter.
IPR005829. Sugar_transporter_CS.
[Graphical view]
PfamPF00083. Sugar_tr. 1 hit.
[Graphical view]
SUPFAMSSF103473. SSF103473. 1 hit.
TIGRFAMsTIGR00898. 2A0119. 1 hit.
PROSITEPS50850. MFS. 1 hit.
PS00216. SUGAR_TRANSPORT_1. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiSLC22A4.
GenomeRNAi6583.
NextBio25617.
PROQ9H015.
SOURCESearch...

Entry information

Entry nameS22A4_HUMAN
AccessionPrimary (citable) accession number: Q9H015
Secondary accession number(s): O14546
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: May 1, 2007
Last modified: July 9, 2014
This is version 117 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM