Sodium-dependent serotonin transporter

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P31645 (SC6A4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 118. History...

Clusters with 100%, 90%, 50% identity |

Documents (5) |

Third-party data

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Sodium-dependent serotonin transporter

Alternative name(s):
5HT transporter
Short name=5HTT
Solute carrier family 6 member 4

Gene names

Name:	SLC6A4
Synonyms:	HTT, SERT

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	630 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.8 Ref.9 Ref.10
Subunit structure	Monomer or homooligomer By similarity. Interacts with TGFB1I1. Interacts (via sialylated form) with MYH9. 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. Interacts with filamentous actin and STX1A By similarity. Interacts (via C-terminus) with VIM. Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with RAB4 (GTP-bound form); the interaction retains transporter molecules intracellularly. Ref.6 Ref.7 Ref.9 Ref.10
Subcellular location	Cell membrane; Multi-pass membrane protein. Endomembrane system; Multi-pass membrane protein. Endosome membrane; Multi-pass membrane protein. Note: Translocates from intracellular locations to the plasma membrane. Density of transporter molecules on the plasma membrane is itself regulated by serotonin. Ref.7 Ref.8 Ref.9 Ref.10
Tissue specificity	Expressed in platelets (at protein level). Ref.8
Induction	Down-regulated when plasma serotonin is elevated. Ref.9 Ref.10
Post-translational modification	Glycosylated; modification with sialylated N-glycans is a requirement for transporters to associate with each other and to function as homooligomeric forms By similarity. Phosphorylated at Ser-611, Thr-613 and Thr-616. Ref.10
Polymorphism	A polymorphism in the promoter region (5-HTT gene-linked polymorphic region, 5-HTTLPR) is located approximately 1 kb upstream of the transcription initiation site and is composed of 16 repeat elements. The polymorphism consists of a 44-bp insertion or deletion involving repeat elements 6 to 8. The short allele is associated with lower transcriptional efficiency of the promoter compared with the long allele. Over half of the Caucasian population has a short allele. Individuals with one or two copies of the short allele exhibit more depressive symptoms, diagnosable depression and suicidality in relation to stressful life events than individuals homozygous for the long allele. The polymorphism Val-425 seems to be linked to a susceptibility to obsessive-compulsive disorder (OCD) [MIM:164230]. Genetic variations in SLC6A4 determine the genetic susceptibility to alcoholism [MIM:103780].
Miscellaneous	This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
Sequence similarities	Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A4 subfamily. [View classification]

Ontologies

Keywords
Biological process	Neurotransmitter transport Symport Transport
Cellular component	Cell membrane Endosome Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane Transmembrane helix
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	response to toxin Inferred from direct assay. Source: UniProtKB serotonin uptake Inferred from direct assay Ref.7 Ref.8 Ref.9 Ref.10. Source: UniProtKB thalamus development Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytosol Inferred from direct assay Ref.10. Source: UniProtKB endomembrane system Inferred from direct assay Ref.8 Ref.9. Source: UniProtKB endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred by curator Ref.10. Source: UniProtKB membrane raft Inferred from direct assay Ref.7. Source: UniProtKB
Molecular function	Rab GTPase binding Inferred from physical interaction Ref.9. Source: UniProtKB actin filament binding Inferred from sequence or structural similarity. Source: UniProtKB serotonin transmembrane transporter activity Inferred from direct assay. Source: UniProtKB serotonin:sodium symporter activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 630

630

Sodium-dependent serotonin transporter

PRO_0000214757

Regions

Topological domain

1 – 87

Cytoplasmic Potential

Transmembrane

88 – 108

Helical; Name=1; Potential

Transmembrane

116 – 135

Helical; Name=2; Potential

Transmembrane

160 – 180

Helical; Name=3; Potential

Topological domain

181 – 252

Extracellular Potential

Transmembrane

253 – 271

Helical; Name=4; Potential

Transmembrane

280 – 297

Helical; Name=5; Potential

Transmembrane

333 – 350

Helical; Name=6; Potential

Transmembrane

362 – 383

Helical; Name=7; Potential

Transmembrane

417 – 436

Helical; Name=8; Potential

Transmembrane

464 – 482

Helical; Name=9; Potential

Transmembrane

498 – 518

Helical; Name=10; Potential

Transmembrane

539 – 558

Helical; Name=11; Potential

Transmembrane

577 – 595

Helical; Name=12; Potential

Topological domain

596 – 630

Cytoplasmic Potential

Region

611 – 630

Required for serotonin uptake activity

Region

616 – 624

Interaction with RAB4A

Amino acid modifications

Modified residue

611

Phosphoserine Potential

Modified residue

613

Phosphothreonine Potential

Modified residue

616

Phosphothreonine Potential

Glycosylation

208

N-linked (GlcNAc...) Potential

Glycosylation

217

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

G → A. Ref.11
Corresponds to variant rs6355 [ dbSNP | Ensembl ].

VAR_014181

Natural variant

201

K → N.
Corresponds to variant rs2228673 [ dbSNP | Ensembl ].

VAR_029158

Natural variant

425

I → L.
Corresponds to variant rs28914832 [ dbSNP | Ensembl ].

VAR_036788

Natural variant

425

I → V Polymorphism linked with susceptibility to obsessive-compulsive disorder; increased serotonin transport capacity. Ref.13 Ref.14

VAR_026751

Natural variant

465

F → L.
Corresponds to variant rs28914833 [ dbSNP | Ensembl ].

VAR_036789

Natural variant

550

L → V.
Corresponds to variant rs28914834 [ dbSNP | Ensembl ].

VAR_036790

Natural variant

605

K → N. Ref.11
Corresponds to variant rs6352 [ dbSNP | Ensembl ].

VAR_014182

Experimental info

Mutagenesis

611

S → A: Loss of 10 % of serotonin uptake activity. Loss of 5 % of serotonin uptake activity; when associated with A-613 and A-616. Ref.10

Mutagenesis

611

S → D: Loss of 61 % of serotonin uptake activity. Loss of 95 % of serotonin uptake activity and lack of association between VIM and the plasma membrane; when associated with D-613 and D-616. Ref.10

Mutagenesis

613

T → A: Loss of 26 % of serotonin uptake activity. Loss of 5 % of serotonin uptake activity; when associated with A-611 and A-616. Ref.10

Mutagenesis

613

T → D: Loss of 26 % of serotonin uptake activity. Loss of 95 % of serotonin uptake activity and lack of association between VIM and the plasma membrane; when associated with D-611 and D-616. Ref.10

Mutagenesis

616

T → A: No change. Loss of 5 % of serotonin uptake activity; when associated with A-611 and A-613. Ref.10

Mutagenesis

616

T → D: No change. Loss of 95 % of serotonin uptake activity and lack of association between VIM and the plasma membrane; when associated with D-611 and D-613. Ref.10

Sequences

Sequence

Length

Mass (Da)

Tools

P31645 [UniParc].

Last modified July 1, 1993. Version 1.
Checksum: 0EB535B0A579BDA2
Show »

FASTA

630

70,325

        10         20         30         40         50         60 
METTPLNSQK QLSACEDGED CQENGVLQKV VPTPGDKVES GQISNGYSAV PSPGAGDDTR 

        70         80         90        100        110        120 
HSIPATTTTL VAELHQGERE TWGKKVDFLL SVIGYAVDLG NVWRFPYICY QNGGGAFLLP 

       130        140        150        160        170        180 
YTIMAIFGGI PLFYMELALG QYHRNGCISI WRKICPIFKG IGYAICIIAF YIASYYNTIM 

       190        200        210        220        230        240 
AWALYYLISS FTDQLPWTSC KNSWNTGNCT NYFSEDNITW TLHSTSPAEE FYTRHVLQIH 

       250        260        270        280        290        300 
RSKGLQDLGG ISWQLALCIM LIFTVIYFSI WKGVKTSGKV VWVTATFPYI ILSVLLVRGA 

       310        320        330        340        350        360 
TLPGAWRGVL FYLKPNWQKL LETGVWIDAA AQIFFSLGPG FGVLLAFASY NKFNNNCYQD 

       370        380        390        400        410        420 
ALVTSVVNCM TSFVSGFVIF TVLGYMAEMR NEDVSEVAKD AGPSLLFITY AEAIANMPAS 

       430        440        450        460        470        480 
TFFAIIFFLM LITLGLDSTF AGLEGVITAV LDEFPHVWAK RRERFVLAVV ITCFFGSLVT 

       490        500        510        520        530        540 
LTFGGAYVVK LLEEYATGPA VLTVALIEAV AVSWFYGITQ FCRDVKEMLG FSPGWFWRIC 

       550        560        570        580        590        600 
WVAISPLFLL FIICSFLMSP PQLRLFQYNY PYWSIILGYC IGTSSFICIP TYIAYRLIIT 

       610        620        630 
PGTFKERIIK SITPETPTEI PCGDIRLNAV

« Hide

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of a cDNA encoding the human brain serotonin transporter." Lesch K.P., Wolozin B.L., Estler H.C., Murphy D.L., Riederer P. J. Neural Transm. 91:67-73(1993) [PubMed: 8452685] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization." Ramamoorthy S., Bauman A.L., Moore K.R., Han H., Yang-Feng T., Chang A.S., Ganapathy V., Blakely R.D. Proc. Natl. Acad. Sci. U.S.A. 90:2542-2546(1993) [PubMed: 7681602] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter." Lesch K.P., Wolozin B.L., Murphy D.L., Reiderer P. J. Neurochem. 60:2319-2322(1993) [PubMed: 7684072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Platelet.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	Bradley C.C., Blakely R.D. Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. Tissue: Placenta.
[6]	"Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the platelet serotonin transporter." Carneiro A.M.D., Blakely R.D. J. Biol. Chem. 281:24769-24780(2006) [PubMed: 16803896] [Abstract] Cited for: INTERACTION WITH TGFB1I1.
[7]	"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: 16870614] [Abstract] Cited for: INTERACTION WITH SCAMP2, SUBCELLULAR LOCATION.
[8]	"Plasma serotonin levels and the platelet serotonin transporter." Brenner B., Harney J.T., Ahmed B.A., Jeffus B.C., Unal R., Mehta J.L., Kilic F. J. Neurochem. 102:206-215(2007) [PubMed: 17506858] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[9]	"Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter." Ahmed B.A., Jeffus B.C., Bukhari S.I., Harney J.T., Unal R., Lupashin V.V., van der Sluijs P., Kilic F. J. Biol. Chem. 283:9388-9398(2008) [PubMed: 18227069] [Abstract] Cited for: FUNCTION, INTERACTION WITH RAB4, SUBCELLULAR LOCATION, INDUCTION BY SEROTONIN.
[10]	"The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network." Ahmed B.A., Bukhari I.A., Jeffus B.C., Harney J.T., Thyparambil S., Ziu E., Fraer M., Rusch N.J., Zimniak P., Lupashin V., Tang D., Kilic F. PLoS ONE 4:E4730-E4730(2009) [PubMed: 19270731] [Abstract] Cited for: FUNCTION, INTERACTION WITH VIM, SUBCELLULAR LOCATION, INDUCTION BY SEROTONIN, MUTAGENESIS OF SER-611; THR-613 AND THR-616, PHOSPHORYLATION AT SER-611; THR-613 AND THR-616.
[11]	"Characterization of single-nucleotide polymorphisms in coding regions of human genes." Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 22:231-238(1999) [PubMed: 10391209] [Abstract] Cited for: VARIANTS ALA-56 AND ASN-605.
[12]	Erratum Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 23:373-373(1999)
[13]	"Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype." Ozaki N., Goldman D., Kaye W.H., Plotnicov K., Greenberg B.D., Lappalainen J., Rudnick G., Murphy D.L. Mol. Psychiatry 8:933-936(2003) [PubMed: 14593431] [Abstract] Cited for: VARIANT VAL-425.
[14]	"A human serotonin transporter mutation causes constitutive activation of transport activity." Kilic F., Murphy D.L., Rudnick G. Mol. Pharmacol. 64:440-446(2003) [PubMed: 12869649] [Abstract] Cited for: CHARACTERIZATION OF VARIANT VAL-425.
[15]	"Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene." Caspi A., Sugden K., Moffitt T.E., Taylor A., Craig I.W., Harrington H., McClay J., Mill J., Martin J., Braithwaite A., Poulton R. Science 301:386-389(2003) [PubMed: 12869766] [Abstract] Cited for: POLYMORPHISM IN THE PROMOTER REGION.
[16]	"Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence." Feinn R., Nellissery M., Kranzler H.R. Am. J. Med. Genet. B Neuropsychiatr. Genet. 133:79-84(2005) [PubMed: 15635638] [Abstract] Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO ALCOHOLISM.
+	Additional computationally mapped references.

Web resources

GeneReviews

SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Serotonin transporter entry

Protein Spotlight

Love, love, love...-Issue 123 of November 2010

Cross-references

Sequence databases
EMBL GenBank DDBJ	X70697 mRNA. Translation: CAA50029.1. L05568 mRNA. Translation: AAA35492.1. BC069484 mRNA. Translation: AAH69484.1. U79746 Genomic DNA. Translation: AAB93475.1.
IPI	IPI00790986.
PIR	A47398.
RefSeq	NP_001036.1. NM_001045.4.
UniGene	Hs.134662.
3D structure databases
ProteinModelPortal	P31645.
SMR	P31645. Positions 78-590.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-577123.
STRING	P31645.
Protein family/group databases
TCDB	2.A.22.1.1. neurotransmitter:sodium symporter (NSS) family.
PTM databases
PhosphoSite	P31645.
Polymorphism databases
DMDM	400630.
Proteomic databases
PRIDE	P31645.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000261707; ENSP00000261707; ENSG00000108576. ENST00000394821; ENSP00000378298; ENSG00000108576. ENST00000401766; ENSP00000385822; ENSG00000108576.
GeneID	6532.
KEGG	hsa:6532.
UCSC	uc002hey.2. human.
Organism-specific databases
CTD	6532.
GeneCards	GC17M028521.
H-InvDB	HIX0039143.
HGNC	HGNC:11050. SLC6A4.
MIM	103780. phenotype. 164230. phenotype. 182138. gene.
neXtProt	NX_P31645.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG09075.
HOGENOM	HBG702834.
HOVERGEN	HBG071421.
InParanoid	P31645.
OrthoDB	EOG447FSX.
PhylomeDB	P31645.
Gene expression databases
ArrayExpress	P31645.
Bgee	P31645.
CleanEx	HS_HTT. HS_SLC6A4.
Genevestigator	P31645.
GermOnline	ENSG00000108576. Homo sapiens.
Family and domain databases
InterPro	IPR000175. Na/ntran_symport. IPR013086. Na/ntran_symport_serotonin_N. [Graphical view]
KO	K05037.
PANTHER	PTHR11616. Na/ntran_symport. 1 hit.
Pfam	PF03491. 5HT_transporter. 1 hit. PF00209. SNF. 1 hit. [Graphical view]
PRINTS	PR01203. 5HTTRANSPORT. PR00176. NANEUSMPORT.
PROSITE	PS00610. NA_NEUROTRAN_SYMP_1. 1 hit. PS00754. NA_NEUROTRAN_SYMP_2. 1 hit. PS50267. NA_NEUROTRAN_SYMP_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P31645.
DrugBank	DB04836. Amineptine. DB00321. Amitriptyline. DB00543. Amoxapine. DB00215. Citalopram. DB01242. Clomipramine. DB00907. Cocaine. DB01151. Desipramine. DB01191. Dexfenfluramine. DB00514. Dextromethorphan. DB01142. Doxepin. DB00476. Duloxetine. DB01175. Escitalopram. DB00472. Fluoxetine. DB00176. Fluvoxamine. DB00458. Imipramine. DB00422. Methylphenidate. DB04896. Milnacipran. DB00805. Minaprine. DB01149. Nefazodone. DB00540. Nortriptyline. DB00715. Paroxetine. DB00191. Phentermine. DB00344. Protriptyline. DB01104. Sertraline. DB01105. Sibutramine. DB01079. Tegaserod. DB00193. Tramadol. DB00656. Trazodone. DB00726. Trimipramine. DB00285. Venlafaxine. DB04832. Zimelidine.
NextBio	25415.
SOURCE	Search...

Entry information

Entry name

SC6A4_HUMAN

Accession

Primary (citable) accession number: P31645

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	July 1, 1993
Last modified:	January 25, 2012
This is version 118 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.

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Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

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

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Protein family/group databases

PTM databases

Polymorphism databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents