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Q9H015

- S22A4_HUMAN

UniProt

Q9H015 - S22A4_HUMAN

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Protein
Solute carrier family 22 member 4
Gene
SLC22A4, ETT, OCTN1, UT2H
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)

pH dependencei

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

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi218 – 2258ATP Reviewed prediction

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. PDZ domain binding Source: BHF-UCL
  3. carnitine transmembrane transporter activity Source: MGI
  4. cation:cation antiporter activity Source: BHF-UCL
  5. nucleotide binding Source: ProtInc
  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
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

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 2020Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei21 – 4121Helical; Name=1; Reviewed prediction
Add
BLAST
Topological domaini42 – 141100Extracellular Reviewed prediction
Add
BLAST
Transmembranei142 – 16221Helical; Name=2; Reviewed prediction
Add
BLAST
Topological domaini163 – 1719Cytoplasmic Reviewed prediction
Transmembranei172 – 19221Helical; Name=3; Reviewed prediction
Add
BLAST
Topological domaini193 – 1975Extracellular Reviewed prediction
Transmembranei198 – 21821Helical; Name=4; Reviewed prediction
Add
BLAST
Topological domaini219 – 23214Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei233 – 25321Helical; Name=5; Reviewed prediction
Add
BLAST
Topological domaini254 – 2574Extracellular Reviewed prediction
Transmembranei258 – 27821Helical; Name=6; Reviewed prediction
Add
BLAST
Topological domaini279 – 33759Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei338 – 35821Helical; Name=7; Reviewed prediction
Add
BLAST
Topological domaini359 – 37113Extracellular Reviewed prediction
Add
BLAST
Transmembranei372 – 39221Helical; Name=8; Reviewed prediction
Add
BLAST
Topological domaini393 – 3997Cytoplasmic Reviewed prediction
Transmembranei400 – 42021Helical; Name=9; Reviewed prediction
Add
BLAST
Topological domaini421 – 4266Extracellular Reviewed prediction
Transmembranei427 – 44721Helical; Name=10; Reviewed prediction
Add
BLAST
Topological domaini448 – 46013Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei461 – 48121Helical; Name=11; Reviewed prediction
Add
BLAST
Topological domaini482 – 4865Extracellular Reviewed prediction
Transmembranei487 – 50721Helical; Name=12; Reviewed prediction
Add
BLAST
Topological domaini508 – 55144Cytoplasmic Reviewed prediction
Add
BLAST

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.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.1 Publication

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 4
PRO_0000220497Add
BLAST

Amino acid modifications

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

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.

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

« Hide

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. 2 Publications
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

« 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: September 3, 2014
This is version 118 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

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

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

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