Q60857 · SC6A4_MOUSE
- ProteinSodium-dependent serotonin transporter
- GeneSlc6a4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids630 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Serotonin transporter that cotransports serotonin with one Na+ ion in exchange for one K+ ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (By similarity) (PubMed:9037532, PubMed:9547354).
Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (PubMed:25600870, PubMed:9547354).
Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (PubMed:27111230).
Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:18317590).
Mechanistically, the transport cycle starts with an outward-open conformation having Na1+ and Cl- sites occupied. The binding of a second extracellular Na2+ ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2+ ion and serotonin are released into the cytosol. Binding of intracellular K+ ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K+ possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1+ and Cl- ions remain bound throughout the transport cycle (By similarity) (PubMed:9037532, PubMed:9547354).
Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na+ ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity).
Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (PubMed:25600870, PubMed:9547354).
Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (PubMed:27111230).
Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:18317590).
Mechanistically, the transport cycle starts with an outward-open conformation having Na1+ and Cl- sites occupied. The binding of a second extracellular Na2+ ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2+ ion and serotonin are released into the cytosol. Binding of intracellular K+ ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K+ possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1+ and Cl- ions remain bound throughout the transport cycle (By similarity) (PubMed:9037532, PubMed:9547354).
Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na+ ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity).
Miscellaneous
This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
Catalytic activity
- H+(in) + K+(in) + Na+(out) + serotonin(out) = H+(out) + K+(out) + Na+(in) + serotonin(in)This reaction proceeds in the forward direction.H+ (in)CHEBI:15378
+ K+ (in)CHEBI:29103+ Na+ (out)CHEBI:29101+ serotonin (out)CHEBI:350546= H+ (out)CHEBI:15378+ K+ (out)CHEBI:29103+ Na+ (in)CHEBI:29101+ serotonin (in)CHEBI:350546
Kinetics
KM | SUBSTRATE | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|---|
403 nM | serotonin |
Vmax | pH | TEMPERATURE[C] | NOTES | EVIDENCE | |
---|---|---|---|---|---|
1.02 pmol/min/mg | for serotonin |
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 94 | Na+ 1 (UniProtKB | ChEBI) | ||||
Sequence: G | ||||||
Binding site | 96 | Na+ 2 (UniProtKB | ChEBI) | ||||
Sequence: A | ||||||
Binding site | 97 | Na+ 1 (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 98 | Na+ 2 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 98 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 101 | Na+ 2 (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 336 | Na+ 2 (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 368 | Na+ 2 (UniProtKB | ChEBI) | ||||
Sequence: N | ||||||
Binding site | 434 | Na+ 1 (UniProtKB | ChEBI) | ||||
Sequence: L | ||||||
Binding site | 437 | Na+ 1 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 438 | Na+ 1 (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 439 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 494 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 495 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 556 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: F | ||||||
Binding site | 559 | serotonin (UniProtKB | ChEBI) | ||||
Sequence: S |
GO annotations
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameSodium-dependent serotonin transporter
- Short namesSERT
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ60857
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Endomembrane system ; Multi-pass membrane protein
Endosome membrane ; Multi-pass membrane protein
Note: Could be part of recycling endosomes. Density of transporter molecules on the plasma membrane is itself regulated by STX1A. Density of transporter molecules on the plasma membrane is also regulated by serotonin (By similarity).
Density of transporter molecules seems to be modulated by ITGAV:ITGB3 (PubMed:29038237).
Density of transporter molecules seems to be modulated by ITGAV:ITGB3 (PubMed:29038237).
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-87 | Cytoplasmic | ||||
Sequence: METTPLNSQKVLSECKDKEDCQENGVLQKGVPTPADKAGPGQISNGYSAVPSTSAGDEAPHSTPAATTTLVAEIHQGERETWGKKMD | ||||||
Transmembrane | 88-112 | Helical; Name=1 | ||||
Sequence: FLLSVIGYAVDLGNIWRFPYICYQN | ||||||
Topological domain | 113-115 | Extracellular | ||||
Sequence: GGG | ||||||
Transmembrane | 116-135 | Helical; Name=2 | ||||
Sequence: AFLLPYTIMAIFGGIPLFYM | ||||||
Topological domain | 136-160 | Cytoplasmic | ||||
Sequence: ELALGQYHRNGCISIWKKICPIFKG | ||||||
Transmembrane | 161-186 | Helical; Name=3 | ||||
Sequence: IGYAICIIAFYIASYYNTIIAWALYY | ||||||
Topological domain | 187-252 | Extracellular | ||||
Sequence: LISSFTDQLPWTSCKNSWNTGNCTNYFAQDNITWTLHSTSPAEEFYLRHVLQIHQSKGLQDLGTIS | ||||||
Transmembrane | 253-271 | Helical; Name=4 | ||||
Sequence: WQLALCIMLIFTIIYFSIW | ||||||
Topological domain | 272-277 | Cytoplasmic | ||||
Sequence: KGVKTS | ||||||
Transmembrane | 278-297 | Helical; Name=5 | ||||
Sequence: GKVVWVTATFPYIVLSVLLV | ||||||
Topological domain | 298-324 | Extracellular | ||||
Sequence: RGATLPGAWRGVVFYLKPNWQKLLETG | ||||||
Transmembrane | 325-347 | Helical; Name=6 | ||||
Sequence: VWVDAAAQIFFSLGPGFGVLLAF | ||||||
Topological domain | 348-360 | Cytoplasmic | ||||
Sequence: ASYNKFNNNCYQD | ||||||
Transmembrane | 361-380 | Helical; Name=7 | ||||
Sequence: ALVTSVVNCMTSFVSGFVIF | ||||||
Topological domain | 381-421 | Extracellular | ||||
Sequence: TVLGYMAEMRNEDVSEVAKDAGPSLLFITYAEAIANMPAST | ||||||
Transmembrane | 422-443 | Helical; Name=8 | ||||
Sequence: FFAIIFFLMLITLGLDSTFAGL | ||||||
Topological domain | 444-463 | Cytoplasmic | ||||
Sequence: EGVITAVLDEFPHIWAKRRE | ||||||
Transmembrane | 464-483 | Helical; Name=9 | ||||
Sequence: WFVLIVVITCILGSLLTLTS | ||||||
Topological domain | 484-494 | Extracellular | ||||
Sequence: GGAYVVTLLEE | ||||||
Transmembrane | 495-516 | Helical; Name=10 | ||||
Sequence: YATGPAVLTVALIEAVVVSWFY | ||||||
Topological domain | 517-538 | Cytoplasmic | ||||
Sequence: GITQFCSDVKEMLGFSPGWFWR | ||||||
Transmembrane | 539-558 | Helical; Name=11 | ||||
Sequence: ICWVAISPLFLLFIICSFLM | ||||||
Topological domain | 559-574 | Extracellular | ||||
Sequence: SPPQLRLFQYNYPHWS | ||||||
Transmembrane | 575-595 | Helical; Name=12 | ||||
Sequence: IILGYCIGTSSVICIPIYIIY | ||||||
Topological domain | 596-630 | Cytoplasmic | ||||
Sequence: RLISTPGTLKERIIKSITPETPTEIPCGDIRMNAV |
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Mutant mice are born at the expected Mendelian rate. Knockdown results in loss of serotonin uptake in synaptosomes of brainstem and cortex, abnormal barrel cortex development, enteric nervous system hyperplasia and reduced peristaltic reflexes.
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 28 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, disulfide bond, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000214759 | 1-630 | Sodium-dependent serotonin transporter | |||
Sequence: METTPLNSQKVLSECKDKEDCQENGVLQKGVPTPADKAGPGQISNGYSAVPSTSAGDEAPHSTPAATTTLVAEIHQGERETWGKKMDFLLSVIGYAVDLGNIWRFPYICYQNGGGAFLLPYTIMAIFGGIPLFYMELALGQYHRNGCISIWKKICPIFKGIGYAICIIAFYIASYYNTIIAWALYYLISSFTDQLPWTSCKNSWNTGNCTNYFAQDNITWTLHSTSPAEEFYLRHVLQIHQSKGLQDLGTISWQLALCIMLIFTIIYFSIWKGVKTSGKVVWVTATFPYIVLSVLLVRGATLPGAWRGVVFYLKPNWQKLLETGVWVDAAAQIFFSLGPGFGVLLAFASYNKFNNNCYQDALVTSVVNCMTSFVSGFVIFTVLGYMAEMRNEDVSEVAKDAGPSLLFITYAEAIANMPASTFFAIIFFLMLITLGLDSTFAGLEGVITAVLDEFPHIWAKRREWFVLIVVITCILGSLLTLTSGGAYVVTLLEEYATGPAVLTVALIEAVVVSWFYGITQFCSDVKEMLGFSPGWFWRICWVAISPLFLLFIICSFLMSPPQLRLFQYNYPHWSIILGYCIGTSSVICIPIYIIYRLISTPGTLKERIIKSITPETPTEIPCGDIRMNAV | ||||||
Modified residue | 47 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 142 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Disulfide bond | 200↔209 | |||||
Sequence: CKNSWNTGNC | ||||||
Glycosylation | 208 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 217 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 276 | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
Phosphorylation at Thr-276 increases 5-HT uptake and is required for cGMP-mediated SERT regulation.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed in the lung, midbrain and brainstem regions (PubMed:9037532).
Expressed in brainstem raphe neurons (PubMed:25600870).
Expressed in brainstem raphe neurons (PubMed:25600870).
Induction
Expressed in a circadian manner in the midbrain with a higher level expression seen during the dark phase (at protein level).
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 (PubMed:20676059).
Expressed during early postnatal brain development in neurons of brainstem and ventrobasal complex (VB) nuclei, including thalamic VB, dorso-lateral geniculate (DLG) nucleus neurons and hippocampal neurons. Expressed in the somatosensory cortex and the brainstem at postnatal day 7 (at protein level) (PubMed:25600870).
Expressed during early postnatal brain development in neurons of brainstem and ventrobasal complex (VB) nuclei, including thalamic VB, dorso-lateral geniculate (DLG) nucleus neurons and hippocampal neurons. Expressed in the somatosensory cortex and the brainstem at postnatal day 7 (at protein level) (PubMed:25600870).
Gene expression databases
Interaction
Subunit
Monomer or homooligomer (By similarity).
Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with filamentous actin and STX1A (By similarity).
Interacts (via the N-terminus) with STX1A (via the H3 domain); this interaction regulates SLC4A6 channel conductance (By similarity).
Interacts with SEC23A, SEC24C and PATJ. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake (PubMed:17452640).
Interacts with TGFB1I1 (PubMed:16803896).
Interacts with ITGAV:ITGB3 (PubMed:29038237).
Interacts (via C-terminus) with ITGB3; this interaction regulates SLC6A4 trafficking (By similarity).
Interacts (via C-terminus) with SCAMP2; the interaction is direct and retains transporter molecules intracellularly. Interacts with filamentous actin and STX1A (By similarity).
Interacts (via the N-terminus) with STX1A (via the H3 domain); this interaction regulates SLC4A6 channel conductance (By similarity).
Interacts with SEC23A, SEC24C and PATJ. Interacts with NOS1; the interaction may diminish the cell surface localization of SERT in the brain and, correspondingly, reduce serotonin reuptake (PubMed:17452640).
Interacts with TGFB1I1 (PubMed:16803896).
Interacts with ITGAV:ITGB3 (PubMed:29038237).
Interacts (via C-terminus) with ITGB3; this interaction regulates SLC6A4 trafficking (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q60857 | Nos1 Q9Z0J4 | 4 | EBI-15633326, EBI-397596 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-63 | Disordered | ||||
Sequence: METTPLNSQKVLSECKDKEDCQENGVLQKGVPTPADKAGPGQISNGYSAVPSTSAGDEAPHST | ||||||
Compositional bias | 45-63 | Polar residues | ||||
Sequence: NGYSAVPSTSAGDEAPHST | ||||||
Region | 616-624 | Interaction with RAB4A | ||||
Sequence: TPTEIPCGD |
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length630
- Mass (Da)70,048
- Last updated2011-07-27 v4
- Checksum2B6ABD26E3288CD0
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
Q5NCR5 | Q5NCR5_MOUSE | Slc6a4 | 158 |
Sequence caution
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 39 | in Ref. 1; AAB67172, 2; CAA70092 and 4; AAA84750 | ||||
Sequence: G → E | ||||||
Compositional bias | 45-63 | Polar residues | ||||
Sequence: NGYSAVPSTSAGDEAPHST | ||||||
Sequence conflict | 152 | in Ref. 1; AAB67172 and 2; CAA70092 | ||||
Sequence: K → R | ||||||
Sequence conflict | 196 | in Ref. 2; CAA70092 | ||||
Sequence: P → Q | ||||||
Sequence conflict | 415 | in Ref. 2; CAA70092 | ||||
Sequence: A → R |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF013604 EMBL· GenBank· DDBJ | AAB67172.1 EMBL· GenBank· DDBJ | mRNA | ||
Y08870 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08871 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08872 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08873 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08874 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08875 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08876 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08877 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08878 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08879 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
Y08880 EMBL· GenBank· DDBJ | CAA70092.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL603842 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
U26452 EMBL· GenBank· DDBJ | AAA84750.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X66119 EMBL· GenBank· DDBJ | - | mRNA | No translation available. |