Sodium-dependent serotonin transporter

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Reviewed, UniProtKB/Swiss-Prot P31645 (SC6A4_HUMAN)

Last modified July 7, 2009. Version 94. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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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) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	630 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Terminates the action of serotonin by its high affinity sodium-dependent reuptake into presynaptic terminals.
Subunit structure	Interacts with TGFB1I1. Ref.6
Subcellular location	Membrane; Multi-pass membrane protein.
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) family.

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Ontologies

Keywords
Biological process	Neurotransmitter transport Symport Transport
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane
PTM	Glycoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	monoamine transport Inferred from direct assay. Source: MGI neurotransmitter uptake Ref.2 Traceable author statement. Source: ProtInc serotonin transport Ref.2 Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Ref.2 Traceable author statement. Source: ProtInc
Molecular function	protein binding Inferred from physical interaction. Source: UniProtKB serotonin transmembrane transporter activity Ref.2 Traceable author statement. Source: ProtInc serotonin:sodium symporter activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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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

1 Potential

Transmembrane

116 – 135

2 Potential

Transmembrane

160 – 180

3 Potential

Topological domain

181 – 252

Extracellular Potential

Transmembrane

253 – 271

4 Potential

Transmembrane

280 – 297

5 Potential

Transmembrane

333 – 350

6 Potential

Transmembrane

362 – 383

7 Potential

Transmembrane

417 – 436

8 Potential

Transmembrane

464 – 482

9 Potential

Transmembrane

498 – 518

10 Potential

Transmembrane

539 – 558

11 Potential

Transmembrane

577 – 595

12 Potential

Topological domain

596 – 630

Cytoplasmic Potential

Amino acid modifications

Glycosylation

208

N-linked (GlcNAc...) Potential

Glycosylation

217

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

G → A: dbSNP rs6355. Ref.7

VAR_014181

Natural variant

201

K → N: dbSNP rs2228673.

VAR_029158

Natural variant

425

I → L: dbSNP rs28914832. Ref.9 Ref.10

VAR_036788

Natural variant

425

I → V Polymorphism linked with susceptibility to obsessive-compulsive disorder; increased serotonin transport capacity. Ref.9 Ref.10

VAR_026751

Natural variant

465

F → L: dbSNP rs28914833.

VAR_036789

Natural variant

550

L → V: dbSNP rs28914834.

VAR_036790

Natural variant

605

K → N: dbSNP rs6352. Ref.7

VAR_014182

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Sequences

Sequence

Length

Mass (Da)

Tools

P31645-1 [UniParc].

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

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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]	"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.
[8]	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)
[9]	"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.
[10]	"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.
[11]	"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.
[12]	"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.

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Web resources

GeneReviews

SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Serotonin transporter entry

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Cross-references

Sequence databases
	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.
UniGene	Hs.591192
3D structure databases
ModBase	Search...
Protein family/group databases
TCDB	2.A.22.1.1. neurotransmitter:sodium symporter (NSS) family.
PTM databases
PhosphoSite	P31645.
Proteomic databases
PRIDE	P31645.
Genome annotation databases
Ensembl	ENSG00000108576. Homo sapiens. [Contig view]
GeneID	6532.
KEGG	hsa:6532.
UCSC	uc002hey.2. human.
Organism-specific databases
GeneCards	GC17M025549.
H-InvDB	HIX0039143.
HGNC	HGNC:11050. SLC6A4.
HPA	CAB000074.
MIM	103780. phenotype. 164230. phenotype. 182138. gene.
PharmGKB	PA312.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P31645.
HOVERGEN	P31645.
Gene expression databases
ArrayExpress	P31645.
Bgee	P31645.
CleanEx	HS_HTT. HS_SLC6A4.
GermOnline	ENSG00000108576. Homo sapiens.
Family and domain databases
InterPro	IPR000175. Na/ntran_symport. IPR013086. Na/ntran_symport_serotonin_N. [Graphical view]
PANTHER	PTHR11616. Na/ntran_symport. 1 hit.
Pfam	PF03491. 5HT_transporter. 1 hit. PF00209. SNF. 1 hit. [Graphical view]
PRINTS	PR01203. 5HTTRANSPORT. PR00176. NANEUSMPORT.
ProDom	PD000448. Na/ntran_symport. 1 hit. [Graphical view] [Entries sharing at least one domain]
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 Resources
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...

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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:	July 7, 2009
This is version 94 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Relevant documents

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 and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein family/group databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents