Q60857 (SC6A4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

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

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

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 By similarity.
Subunit structure	Monomer or homooligomer 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 GTP-bound RAB4 (GTP-bound form); the interaction retains transporter molecules intracellularly. Interacts (via sialylated form) with MYH9. Interacts with filamentous actin and STX1A By similarity. 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 TGFB1I1. Ref.7 Ref.8
Subcellular location	Cell membrane; Multi-pass membrane protein By similarity. Endomembrane system By similarity; Multi-pass membrane protein. Endosome membrane By similarity. Note: Translocates from intracellular locations to the plasma membrane. Density of transporter molecules on the plasma membrane is itself regulated by serotonin By similarity.
Developmental stage	Expressed in the uncrossed ipsilateral retinal ganglion cells (iRGCs) of the peripheral ventrotemporal (VT) region segment in the retina at 16.5 dpc. Ref.9
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. 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 similarity.
Disruption phenotype	Loss of serotonin uptake. Ref.6
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]
Sequence caution	The sequence X66119 differs from that shown. Reason: Frameshift at position 195.

Ontologies

Keywords
Biological process	Neurotransmitter transport Symport Transport
Cellular component	Cell membrane Endosome Membrane
Domain	Transmembrane Transmembrane helix
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	brain morphogenesis Inferred from mutant phenotype PubMed 19208814. Source: BHF-UCL cellular response to cGMP Inferred from electronic annotation. Source: Compara cellular response to organic substance Inferred from direct assay PubMed 18794345. Source: MGI cellular response to retinoic acid Inferred from electronic annotation. Source: Compara circadian rhythm Inferred from electronic annotation. Source: Compara memory Inferred from electronic annotation. Source: Compara negative regulation of cerebellar granule cell precursor proliferation Inferred from electronic annotation. Source: Compara negative regulation of neuron differentiation Inferred from electronic annotation. Source: Compara negative regulation of organ growth Inferred from mutant phenotype PubMed 19208814. Source: BHF-UCL negative regulation of synaptic transmission, dopaminergic Inferred from electronic annotation. Source: Compara positive regulation of cell cycle Inferred from mutant phenotype PubMed 19308295. Source: UniProtKB positive regulation of gene expression Inferred from mutant phenotype PubMed 19308295. Source: UniProtKB protein homooligomerization Inferred from electronic annotation. Source: Compara protein oligomerization Inferred from sequence or structural similarity. Source: UniProtKB response to drug Inferred from electronic annotation. Source: Compara response to estradiol stimulus Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara response to nutrient Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara serotonin uptake Inferred from direct assay Ref.8. Source: UniProtKB social behavior Inferred from genetic interaction PubMed 19208814. Source: BHF-UCL sperm ejaculation Inferred from electronic annotation. Source: Compara thalamus development Inferred from electronic annotation. Source: Compara vasoconstriction Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Inferred from electronic annotation. Source: Compara endomembrane system Inferred from sequence or structural similarity. Source: UniProtKB endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from electronic annotation. Source: InterPro membrane raft Inferred from electronic annotation. Source: Compara neuron projection Inferred from electronic annotation. Source: Compara plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	actin filament binding Inferred from sequence or structural similarity. Source: UniProtKB cocaine binding Inferred from electronic annotation. Source: Compara serotonin transmembrane transporter activity Inferred from sequence or structural similarity. Source: UniProtKB serotonin:sodium symporter activity Inferred from sequence or structural similarity. 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_0000214759
Regions
	Topological domain	1 – 87	87	Cytoplasmic Potential
	Transmembrane	88 – 108	21	Helical; Name=1; Potential
	Transmembrane	116 – 135	20	Helical; Name=2; Potential
	Transmembrane	160 – 180	21	Helical; Name=3; Potential
	Topological domain	181 – 252	72	Extracellular Potential
	Transmembrane	253 – 271	19	Helical; Name=4; Potential
	Transmembrane	280 – 297	18	Helical; Name=5; Potential
	Transmembrane	333 – 350	18	Helical; Name=6; Potential
	Transmembrane	362 – 383	22	Helical; Name=7; Potential
	Transmembrane	417 – 436	20	Helical; Name=8; Potential
	Transmembrane	464 – 482	19	Helical; Name=9; Potential
	Transmembrane	498 – 518	21	Helical; Name=10; Potential
	Transmembrane	539 – 558	20	Helical; Name=11; Potential
	Transmembrane	577 – 595	19	Helical; Name=12; Potential
	Topological domain	596 – 630	35	Cytoplasmic Potential
	Region	611 – 630	20	Required for serotonin uptake activity By similarity
	Region	616 – 624	9	Interaction with RAB4A By similarity
Amino acid modifications
	Modified residue	47	1	Phosphotyrosine By similarity
	Modified residue	142	1	Phosphotyrosine By similarity
	Modified residue	276	1	Phosphothreonine By similarity
	Modified residue	611	1	Phosphoserine Potential
	Modified residue	613	1	Phosphothreonine Potential
	Modified residue	616	1	Phosphothreonine Potential
	Glycosylation	208	1	N-linked (GlcNAc...) Potential
	Glycosylation	217	1	N-linked (GlcNAc...) Potential
Experimental info
	Sequence conflict	39	1	G → E in AAB67172. Ref.1
	Sequence conflict	39	1	G → E in CAA70092. Ref.2
	Sequence conflict	39	1	G → E in AAA84750. Ref.4
	Sequence conflict	152	1	K → R in AAB67172. Ref.1
	Sequence conflict	152	1	K → R in CAA70092. Ref.2
	Sequence conflict	196	1	P → Q in CAA70092. Ref.2
	Sequence conflict	415	1	A → R in CAA70092. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q60857 [UniParc]. Last modified July 27, 2011. Version 4. Checksum: 2B6ABD26E3288CD0	FASTA	630	70,048
	10 20 30 40 50 60 METTPLNSQK VLSECKDKED CQENGVLQKG VPTPADKAGP GQISNGYSAV PSTSAGDEAP 70 80 90 100 110 120 HSTPAATTTL VAEIHQGERE TWGKKMDFLL SVIGYAVDLG NIWRFPYICY QNGGGAFLLP 130 140 150 160 170 180 YTIMAIFGGI PLFYMELALG QYHRNGCISI WKKICPIFKG IGYAICIIAF YIASYYNTII 190 200 210 220 230 240 AWALYYLISS FTDQLPWTSC KNSWNTGNCT NYFAQDNITW TLHSTSPAEE FYLRHVLQIH 250 260 270 280 290 300 QSKGLQDLGT ISWQLALCIM LIFTIIYFSI WKGVKTSGKV VWVTATFPYI VLSVLLVRGA 310 320 330 340 350 360 TLPGAWRGVV FYLKPNWQKL LETGVWVDAA AQIFFSLGPG FGVLLAFASY NKFNNNCYQD 370 380 390 400 410 420 ALVTSVVNCM TSFVSGFVIF TVLGYMAEMR NEDVSEVAKD AGPSLLFITY AEAIANMPAS 430 440 450 460 470 480 TFFAIIFFLM LITLGLDSTF AGLEGVITAV LDEFPHIWAK RREWFVLIVV ITCILGSLLT 490 500 510 520 530 540 LTSGGAYVVT LLEEYATGPA VLTVALIEAV VVSWFYGITQ FCSDVKEMLG FSPGWFWRIC 550 560 570 580 590 600 WVAISPLFLL FIICSFLMSP PQLRLFQYNY PHWSIILGYC IGTSSVICIP IYIIYRLIST 610 620 630 PGTLKERIIK SITPETPTEI PCGDIRMNAV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of the mouse serotonin transporter." Chang A.S., Chang S.M., Starnes D.M., Schroeter S., Bauman A.L., Blakely R.D. Brain Res. Mol. Brain Res. 43:185-192(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Gene structure and 5'-flanking regulatory region of the murine serotonin transporter." Bengel D., Heils A., Petri S., Seemann M., Glatz K., Andrews A., Murphy D.L., Lesch K.P. Brain Res. Mol. Brain Res. 44:286-292(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: 129.
[3]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[4]	Saito N., Sakai N., Kobayashi S., Fujimoto M., Morikawa O., Ikegaki N. Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. Strain: BALB/c.
[5]	"Murine serotonin transporter: sequence and localization to chromosome 11." Gregor P., Patel A., Shimada S., Lin C.L., Rochelle J.M., Kitayama S., Seldin M.F., Uhl G.R. Mamm. Genome 4:283-284(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 69-630.
[6]	"Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ('Ecstasy') in serotonin transporter-deficient mice." Bengel D., Murphy D.L., Andrews A.M., Wichems C.H., Feltner D., Heils A., Mossner R., Westphal H., Lesch K.P. Mol. Pharmacol. 53:649-655(1998) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[7]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TGFB1I1.
[8]	"Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity." Chanrion B., Mannoury la Cour C., Bertaso F., Lerner-Natoli M., Freissmuth M., Millan M.J., Bockaert J., Marin P. Proc. Natl. Acad. Sci. U.S.A. 104:8119-8124(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NOS1; SEC23A; SEC24C AND INADL.
[9]	"Zic2 regulates the expression of Sert to modulate eye-specific refinement at the visual targets." Garcia-Frigola C., Herrera E. EMBO J. 29:3170-3183(2010) [PubMed] [Europe PMC] [Abstract] Cited for: DEVELOPMENTAL STAGE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF013604 mRNA. Translation: AAB67172.1. Y08870 , Y08871, Y08872, Y08873, Y08874, Y08875, Y08876, Y08877, Y08878, Y08879, Y08880 Genomic DNA. Translation: CAA70092.1. AL603842 Genomic DNA. Translation: CAI35067.1. U26452 Genomic DNA. Translation: AAA84750.1. X66119 mRNA. No translation available.
IPI	IPI00310728.
RefSeq	NP_034614.2. NM_010484.2.
UniGene	Mm.300318.
3D structure databases
ProteinModelPortal	Q60857.
SMR	Q60857. Positions 79-590.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000021195.
PTM databases
PhosphoSite	Q60857.
Proteomic databases
PaxDb	Q60857.
PRIDE	Q60857.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000021195; ENSMUSP00000021195; ENSMUSG00000020838. ENSMUST00000108402; ENSMUSP00000104039; ENSMUSG00000020838.
GeneID	15567.
KEGG	mmu:15567.
Organism-specific databases
CTD	6532.
MGI	MGI:96285. Slc6a4.
Phylogenomic databases
eggNOG	COG0733.
GeneTree	ENSGT00690000101944.
HOGENOM	HOG000116406.
HOVERGEN	HBG071421.
InParanoid	Q5NCR6.
KO	K05037.
OMA	TRHVLQI.
OrthoDB	EOG447FSX.
Gene expression databases
ArrayExpress	Q60857.
Bgee	Q60857.
CleanEx	MM_HTT.
Genevestigator	Q60857.
GermOnline	ENSMUSG00000020838. Mus musculus.
Family and domain databases
InterPro	IPR000175. Na/ntran_symport. IPR013086. Na/ntran_symport_serotonin_N. [Graphical view]
PANTHER	PTHR11616. PTHR11616. 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	Q60857.
ChEMBL	CHEMBL4642.
NextBio	288538.
SOURCE	Search...

Entry information

Entry name

SC6A4_MOUSE

Accession

Primary (citable) accession number: Q60857
Secondary accession number(s): O35241, Q5NCR6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	July 27, 2011
Last modified:	May 1, 2013
This is version 106 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program