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Protein

Sodium-dependent serotonin transporter

Gene

Slc6a4

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.5 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi94 – 941Sodium 1; via carbonyl oxygenBy similarity
Metal bindingi96 – 961Sodium 2; via carbonyl oxygenBy similarity
Metal bindingi97 – 971Sodium 1; via carbonyl oxygenBy similarity
Metal bindingi101 – 1011Sodium 2By similarity
Metal bindingi336 – 3361Sodium 2By similarity
Metal bindingi368 – 3681Sodium 2By similarity
Metal bindingi434 – 4341Sodium 1; via carbonyl oxygenBy similarity
Metal bindingi437 – 4371Sodium 1By similarity
Metal bindingi438 – 4381Sodium 1By similarity

GO - Molecular functioni

  • actin filament binding Source: UniProtKB
  • cocaine binding Source: RGD
  • metal ion binding Source: UniProtKB-KW
  • myosin binding Source: UniProtKB
  • protein homodimerization activity Source: RGD
  • serotonin:sodium symporter activity Source: UniProtKB
  • serotonin transmembrane transporter activity Source: UniProtKB
  • syntaxin-1 binding Source: UniProtKB

GO - Biological processi

  • brain development Source: RGD
  • brain morphogenesis Source: Ensembl
  • cellular response to cGMP Source: RGD
  • cellular response to retinoic acid Source: RGD
  • circadian rhythm Source: RGD
  • locomotory behavior Source: RGD
  • memory Source: RGD
  • negative regulation of cerebellar granule cell precursor proliferation Source: RGD
  • negative regulation of neuron differentiation Source: RGD
  • negative regulation of organ growth Source: Ensembl
  • negative regulation of synaptic transmission, dopaminergic Source: RGD
  • positive regulation of cell cycle Source: Ensembl
  • positive regulation of gene expression Source: Ensembl
  • protein homooligomerization Source: UniProtKB
  • protein oligomerization Source: UniProtKB
  • response to drug Source: RGD
  • response to estradiol Source: RGD
  • response to hypoxia Source: RGD
  • response to nutrient Source: RGD
  • response to organic substance Source: RGD
  • response to toxic substance Source: Ensembl
  • serotonin transport Source: UniProtKB
  • serotonin uptake Source: UniProtKB
  • social behavior Source: Ensembl
  • sperm ejaculation Source: RGD
  • thalamus development Source: Ensembl
  • vasoconstriction Source: RGD
Complete GO annotation...

Keywords - Biological processi

Neurotransmitter transport, Symport, Transport

Keywords - Ligandi

Metal-binding, Sodium

Names & Taxonomyi

Protein namesi
Recommended name:
Sodium-dependent serotonin transporter
Short name:
SERT1 Publication
Alternative name(s):
5HT transporter
Short name:
5HTT
Solute carrier family 6 member 4
Gene namesi
Name:Slc6a4
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 10

Organism-specific databases

RGDi3714. Slc6a4.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 8787CytoplasmicCuratedAdd
BLAST
Transmembranei88 – 11225Helical; Name=1By similarityAdd
BLAST
Topological domaini113 – 1153ExtracellularCurated
Transmembranei116 – 13520Helical; Name=2By similarityAdd
BLAST
Topological domaini136 – 16025CytoplasmicCuratedAdd
BLAST
Transmembranei161 – 18626Helical; Name=3By similarityAdd
BLAST
Topological domaini187 – 25266ExtracellularCuratedAdd
BLAST
Transmembranei253 – 27119Helical; Name=4By similarityAdd
BLAST
Topological domaini272 – 2776CytoplasmicCurated
Transmembranei278 – 29720Helical; Name=5By similarityAdd
BLAST
Topological domaini298 – 32427ExtracellularCuratedAdd
BLAST
Transmembranei325 – 34723Helical; Name=6By similarityAdd
BLAST
Topological domaini348 – 36013CytoplasmicCuratedAdd
BLAST
Transmembranei361 – 38020Helical; Name=7By similarityAdd
BLAST
Topological domaini381 – 42141ExtracellularCuratedAdd
BLAST
Transmembranei422 – 44322Helical; Name=8By similarityAdd
BLAST
Topological domaini444 – 46320CytoplasmicCuratedAdd
BLAST
Transmembranei464 – 48320Helical; Name=9By similarityAdd
BLAST
Topological domaini484 – 49411ExtracellularCuratedAdd
BLAST
Transmembranei495 – 51622Helical; Name=10By similarityAdd
BLAST
Topological domaini517 – 53822CytoplasmicCuratedAdd
BLAST
Transmembranei539 – 55820Helical; Name=11By similarityAdd
BLAST
Topological domaini559 – 57416ExtracellularCuratedAdd
BLAST
Transmembranei575 – 59521Helical; Name=12By similarityAdd
BLAST
Topological domaini596 – 63035CytoplasmicCuratedAdd
BLAST

GO - Cellular componenti

  • cytosol Source: Ensembl
  • endomembrane system Source: UniProtKB
  • endosome membrane Source: UniProtKB-SubCell
  • integral component of plasma membrane Source: GO_Central
  • membrane raft Source: RGD
  • neuron projection Source: RGD
  • plasma membrane Source: UniProtKB
  • presynapse Source: GOC
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi109 – 1091C → A: Cocaine is effective at blocking transport. 1 Publication
Mutagenesisi172 – 1721I → C: Cocaine is effective at blocking transport. 1 Publication
Mutagenesisi208 – 2081N → Q: No change in transport function. Important decrease of transport function and serotonin uptake function; when associated with Q-217. 1 Publication
Mutagenesisi217 – 2171N → Q: No change in transport function. Important decrease of transport function and serotonin uptake function; when associated with Q-208. 1 Publication

Chemistry

ChEMBLiCHEMBL2094252.
GuidetoPHARMACOLOGYi928.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 630630Sodium-dependent serotonin transporterPRO_0000214760Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei47 – 471PhosphotyrosineBy similarity
Modified residuei142 – 1421PhosphotyrosineBy similarity
Disulfide bondi200 ↔ 209By similarity
Glycosylationi208 – 2081N-linked (GlcNAc...)1 Publication
Glycosylationi217 – 2171N-linked (GlcNAc...)1 Publication
Modified residuei276 – 2761Phosphothreonine1 Publication
Modified residuei611 – 6111PhosphoserineSequence analysisBy similarity
Modified residuei613 – 6131PhosphothreonineSequence analysisBy similarity
Modified residuei616 – 6161PhosphothreonineSequence analysisBy similarity

Post-translational modificationi

Glycosylated; modification with sialylated N-glycans is a requirement for transporters to associate with each other and to function as homooligomeric forms.1 Publication
Phosphorylation upon PKC stimulation modifies the SERT distribution and density in the membrane, and diminishes the uptake capacity (By similarity). Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.By similarity1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiP31652.

PTM databases

iPTMnetiP31652.
SwissPalmiP31652.

Expressioni

Gene expression databases

GenevisibleiP31652. RN.

Interactioni

Subunit structurei

Monomer or homooligomer. Interacts with TGFB1I1. Interacts (via C-terminus) with VIM. Interacts with RAB4 (GTP-bound form); the interaction retains transporter molecules intracellularly. Interacts with SEC23A, SEC24C and INADL. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake (By similarity). Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with filamentous actin and STX1A. Interacts (via sialylated form) with MYH9.By similarity5 Publications

GO - Molecular functioni

  • actin filament binding Source: UniProtKB
  • myosin binding Source: UniProtKB
  • protein homodimerization activity Source: RGD
  • syntaxin-1 binding Source: UniProtKB

Protein-protein interaction databases

IntActiP31652. 1 interaction.
STRINGi10116.ENSRNOP00000004717.

Chemistry

BindingDBiP31652.

Structurei

3D structure databases

ProteinModelPortaliP31652.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni611 – 63020Required for serotonin uptake activityBy similarityAdd
BLAST
Regioni616 – 6249Interaction with RAB4ABy similarity

Sequence similaritiesi

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3659. Eukaryota.
COG0733. LUCA.
GeneTreeiENSGT00760000118857.
HOGENOMiHOG000116406.
HOVERGENiHBG071421.
InParanoidiP31652.
KOiK05037.
OMAiCRDVKEM.
OrthoDBiEOG793B71.
PhylomeDBiP31652.
TreeFamiTF343812.

Family and domain databases

InterProiIPR000175. Na/ntran_symport.
IPR013086. Na/ntran_symport_serotonin_N.
[Graphical view]
PANTHERiPTHR11616. PTHR11616. 2 hits.
PfamiPF03491. 5HT_transport_N. 1 hit.
PF00209. SNF. 1 hit.
[Graphical view]
PRINTSiPR01203. 5HTTRANSPORT.
PR00176. NANEUSMPORT.
PROSITEiPS00610. NA_NEUROTRAN_SYMP_1. 1 hit.
PS00754. NA_NEUROTRAN_SYMP_2. 1 hit.
PS50267. NA_NEUROTRAN_SYMP_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P31652-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
METTPLNSQK VLSECKDRED CQENGVLQKG VPTTADRAEP SQISNGYSAV
60 70 80 90 100
PSTSAGDEAS HSIPAATTTL VAEIRQGERE TWGKKMDFLL SVIGYAVDLG
110 120 130 140 150
NIWRFPYICY QNGGGAFLLP YTIMAIFGGI PLFYMELALG QYHRNGCISI
160 170 180 190 200
WRKICPIFKG IGYAICIIAF YIASYYNTII AWALYYLISS LTDRLPWTSC
210 220 230 240 250
TNSWNTGNCT NYFAQDNITW TLHSTSPAEE FYLRHVLQIH QSKGLQDLGT
260 270 280 290 300
ISWQLTLCIV LIFTVIYFSI WKGVKTSGKV VWVTATFPYI VLSVLLVRGA
310 320 330 340 350
TLPGAWRGVV FYLKPNWQKL LETGVWVDAA AQIFFSLGPG FGVLLAFASY
360 370 380 390 400
NKFNNNCYQD ALVTSVVNCM TSFVSGFVIF TVLGYMAEMR NEDVSEVAKD
410 420 430 440 450
AGPSLLFITY AEAIANMPAS TFFAIIFFLM LITLGLDSTF AGLEGVITAV
460 470 480 490 500
LDEFPHIWAK RREWFVLIVV ITCVLGSLLT LTSGGAYVVT LLEEYATGPA
510 520 530 540 550
VLTVALIEAV AVSWFYGITQ FCSDVKEMLG FSPGWFWRIC WVAISPLFLL
560 570 580 590 600
FIICSFLMSP PQLRLFQYNY PHWSIVLGYC IGMSSVICIP TYIIYRLIST
610 620 630
PGTLKERIIK SITPETPTEI PCGDIRMNAV
Length:630
Mass (Da):70,172
Last modified:July 1, 1993 - v1
Checksum:i44DA7C5888C403EE
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti415 – 4151A → G in AAA42186 (PubMed:1948036).Curated
Sequence conflicti533 – 5364PGWF → GMV in AAA42186 (PubMed:1948036).Curated
Sequence conflicti621 – 63010PCGDIRMNAV → RVGHPHECCVTHPGRGHLFP ATSLSSEKPTGLLL in AAA42186 (PubMed:1948036).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63995 mRNA. Translation: CAA45401.1.
X63253 mRNA. Translation: CAA44913.1.
M79450 mRNA. Translation: AAA42186.1.
Y11024 mRNA. Translation: CAA71909.1.
PIRiS19585.
S30604.
RefSeqiNP_037166.2. NM_013034.4.
XP_008766172.1. XM_008767950.1.
UniGeneiRn.1663.

Genome annotation databases

EnsembliENSRNOT00000004717; ENSRNOP00000004717; ENSRNOG00000003476.
GeneIDi25553.
KEGGirno:25553.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63995 mRNA. Translation: CAA45401.1.
X63253 mRNA. Translation: CAA44913.1.
M79450 mRNA. Translation: AAA42186.1.
Y11024 mRNA. Translation: CAA71909.1.
PIRiS19585.
S30604.
RefSeqiNP_037166.2. NM_013034.4.
XP_008766172.1. XM_008767950.1.
UniGeneiRn.1663.

3D structure databases

ProteinModelPortaliP31652.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP31652. 1 interaction.
STRINGi10116.ENSRNOP00000004717.

Chemistry

BindingDBiP31652.
ChEMBLiCHEMBL2094252.
GuidetoPHARMACOLOGYi928.

PTM databases

iPTMnetiP31652.
SwissPalmiP31652.

Proteomic databases

PaxDbiP31652.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000004717; ENSRNOP00000004717; ENSRNOG00000003476.
GeneIDi25553.
KEGGirno:25553.

Organism-specific databases

CTDi6532.
RGDi3714. Slc6a4.

Phylogenomic databases

eggNOGiKOG3659. Eukaryota.
COG0733. LUCA.
GeneTreeiENSGT00760000118857.
HOGENOMiHOG000116406.
HOVERGENiHBG071421.
InParanoidiP31652.
KOiK05037.
OMAiCRDVKEM.
OrthoDBiEOG793B71.
PhylomeDBiP31652.
TreeFamiTF343812.

Miscellaneous databases

PROiP31652.

Gene expression databases

GenevisibleiP31652. RN.

Family and domain databases

InterProiIPR000175. Na/ntran_symport.
IPR013086. Na/ntran_symport_serotonin_N.
[Graphical view]
PANTHERiPTHR11616. PTHR11616. 2 hits.
PfamiPF03491. 5HT_transport_N. 1 hit.
PF00209. SNF. 1 hit.
[Graphical view]
PRINTSiPR01203. 5HTTRANSPORT.
PR00176. NANEUSMPORT.
PROSITEiPS00610. NA_NEUROTRAN_SYMP_1. 1 hit.
PS00754. NA_NEUROTRAN_SYMP_2. 1 hit.
PS50267. NA_NEUROTRAN_SYMP_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Isolation of cDNAs encoding a novel member of the neurotransmitter transporter gene family."
    Mayser W., Betz H., Schloss P.
    FEBS Lett. 295:203-206(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Wistar.
  2. "Cloning and expression of a functional serotonin transporter from rat brain."
    Blakely R.D., Berson H.E., Fremeau R.T. Jr., Caron M.G., Peek M.M., Prince H.K., Bardley C.C.
    Nature 354:66-70(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
    Tissue: Brain stem.
  3. Blakely R.D.
    Submitted (JUL-1992) to the EMBL/GenBank/DDBJ databases
    Cited for: SEQUENCE REVISION.
  4. "Cloning of a serotonin transporter affected by antidepressants."
    Hoffman B.J., Mezey E., Brownstein M.J.
    Science 254:579-580(1991) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION.
  5. Gonzalez A.M., Smith A.P.L., Emery C.J., Higenbottam T.W.
    Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Fawn hooded.
  6. "Oligomerization of serotonin transporter and its functional consequences."
    Kilic F., Rudnick G.
    Proc. Natl. Acad. Sci. U.S.A. 97:3106-3111(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: MUTAGENESIS OF CYS-109 AND ILE-172, FUNCTION, SUBCELLULAR LOCATION, SUBUNIT.
  7. "Regulation of the serotonin transporter by interacting proteins."
    Haase J., Killian A.M., Magnani F., Williams C.
    Biochem. Soc. Trans. 29:722-728(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH STX1A, SUBCELLULAR LOCATION.
  8. "Glycosyl modification facilitates homo- and hetero-oligomerization of the serotonin transporter. A specific role for sialic acid residues."
    Ozaslan D., Wang S., Ahmed B.A., Kocabas A.M., McCastlain J.C., Bene A., Kilic F.
    J. Biol. Chem. 278:43991-44000(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION, FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-208 AND ASN-217, SUBUNIT, INTERACTION WITH MYH9.
  9. "Role of C-terminal region in the functional regulation of rat serotonin transporter (SERT)."
    Mochizuki H., Amano T., Seki T., Matsubayashi H., Mitsuhata C., Morita K., Kitayama S., Dohi T., Mishima H.K., Sakai N.
    Neurochem. Int. 46:93-105(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH FILAMENTOUS ACTIN.
  10. "Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2."
    Mueller H.K., Wiborg O., Haase J.
    J. Biol. Chem. 281:28901-28909(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH SCAMP2, SUBCELLULAR LOCATION.
  11. "Phosphorylation of threonine residue 276 is required for acute regulation of serotonin transporter by cyclic GMP."
    Ramamoorthy S., Samuvel D.J., Buck E.R., Rudnick G., Jayanthi L.D.
    J. Biol. Chem. 282:11639-11647(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT THR-276.

Entry informationi

Entry nameiSC6A4_RAT
AccessioniPrimary (citable) accession number: P31652
Secondary accession number(s): P23976
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 1, 1993
Last sequence update: July 1, 1993
Last modified: July 6, 2016
This is version 134 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

This protein is the target of psychomotor stimulants such as amphetamines or cocaine.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.