ID SC6A4_HUMAN Reviewed; 630 AA. AC P31645; Q5EE02; DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1993, sequence version 1. DT 27-MAR-2024, entry version 217. DE RecName: Full=Sodium-dependent serotonin transporter; DE Short=SERT {ECO:0000250|UniProtKB:P31652}; DE AltName: Full=5HT transporter; DE Short=5HTT; DE AltName: Full=Solute carrier family 6 member 4; GN Name=SLC6A4; Synonyms=HTT, SERT; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=8452685; DOI=10.1007/bf01244919; RA Lesch K.P., Wolozin B.L., Estler H.C., Murphy D.L., Riederer P.; RT "Isolation of a cDNA encoding the human brain serotonin transporter."; RL J. Neural Transm. 91:67-73(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=7681602; DOI=10.1073/pnas.90.6.2542; RA Ramamoorthy S., Bauman A.L., Moore K.R., Han H., Yang-Feng T., Chang A.S., RA Ganapathy V., Blakely R.D.; RT "Antidepressant- and cocaine-sensitive human serotonin transporter: RT molecular cloning, expression, and chromosomal localization."; RL Proc. Natl. Acad. Sci. U.S.A. 90:2542-2546(1993). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Platelet; RX PubMed=7684072; DOI=10.1111/j.1471-4159.1993.tb03522.x; RA Lesch K.P., Wolozin B.L., Murphy D.L., Reiderer P.; RT "Primary structure of the human platelet serotonin uptake site: identity RT with the brain serotonin transporter."; RL J. Neurochem. 60:2319-2322(1993). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=16601320; RA Iceta R., Mesonero J.E., Aramayona J.J., Alcalde A.I.; RT "Molecular characterization and intracellular regulation of the human RT serotonin transporter in Caco-2 cells."; RL J. Physiol. Pharmacol. 57:119-130(2006). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (AUG-2007) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-114. RC TISSUE=Placenta; RA Bradley C.C., Blakely R.D.; RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-317 (ISOFORM 2). RC TISSUE=Lung; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=10407194; DOI=10.1016/s0169-328x(99)00178-3; RA Mortensen O.V., Kristensen A.S., Rudnick G., Wiborg O.; RT "Molecular cloning, expression and characterization of a bovine serotonin RT transporter."; RL Brain Res. Mol. Brain Res. 71:120-126(1999). RN [10] RP INTERACTION WITH TGFB1I1. RX PubMed=16803896; DOI=10.1074/jbc.m603877200; RA Carneiro A.M.D., Blakely R.D.; RT "Serotonin-, protein kinase C-, and Hic-5-associated redistribution of the RT platelet serotonin transporter."; RL J. Biol. Chem. 281:24769-24780(2006). RN [11] RP INTERACTION WITH SCAMP2, AND SUBCELLULAR LOCATION. RX PubMed=16870614; DOI=10.1074/jbc.m602848200; RA Mueller H.K., Wiborg O., Haase J.; RT "Subcellular redistribution of the serotonin transporter by secretory RT carrier membrane protein 2."; RL J. Biol. Chem. 281:28901-28909(2006). RN [12] RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, TRANSPORTER ACTIVITY, RP AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=17506858; DOI=10.1111/j.1471-4159.2007.04542.x; RA Brenner B., Harney J.T., Ahmed B.A., Jeffus B.C., Unal R., Mehta J.L., RA Kilic F.; RT "Plasma serotonin levels and the platelet serotonin transporter."; RL J. Neurochem. 102:206-215(2007). RN [13] RP PHOSPHORYLATION AT THR-276, AND VARIANT VAL-425. RX PubMed=17913921; DOI=10.1523/jneurosci.0034-07.2007; RA Zhang Y.W., Gesmonde J., Ramamoorthy S., Rudnick G.; RT "Serotonin transporter phosphorylation by cGMP-dependent protein kinase is RT altered by a mutation associated with obsessive compulsive disorder."; RL J. Neurosci. 27:10878-10886(2007). RN [14] RP RETRACTED PAPER. RX PubMed=18227069; DOI=10.1074/jbc.m706367200; RA Ahmed B.A., Jeffus B.C., Bukhari S.I., Harney J.T., Unal R., Lupashin V.V., RA van der Sluijs P., Kilic F.; RT "Serotonin transamidates Rab4 and facilitates its binding to the C terminus RT of serotonin transporter."; RL J. Biol. Chem. 283:9388-9398(2008). RN [15] RP RETRACTION NOTICE OF PUBMED:18227069. RX PubMed=31201246; DOI=10.1074/jbc.w119.009467; RA Ahmed B.A., Jeffus B.C., Bukhari S.I.A., Harney J.T., Unal R., RA Lupashin V.V., van der Sluijs P., Kilic F.; RL J. Biol. Chem. 294:9658-9658(2019). RN [16] RP RETRACTED PAPER. RX PubMed=19270731; DOI=10.1371/journal.pone.0004730; RA Ahmed B.A., Bukhari I.A., Jeffus B.C., Harney J.T., Thyparambil S., Ziu E., RA Fraer M., Rusch N.J., Zimniak P., Lupashin V., Tang D., Kilic F.; RT "The cellular distribution of serotonin transporter is impeded on RT serotonin-altered vimentin network."; RL PLoS ONE 4:E4730-E4730(2009). RN [17] RP RETRACTION NOTICE OF PUBMED:19270731. RX PubMed=30707744; DOI=10.1371/journal.pone.0211966; RA Ahmed B.A., Bukhari I.A., Jeffus B.C., Harney J.T., Thyparambil S., Ziu E., RA Fraer M., Rusch N.J., Zimniak P., Lupashin V., Tang D., Kilic F.; RT "Retraction: The Cellular Distribution of Serotonin Transporter Is Impeded RT on Serotonin-Altered Vimentin Network."; RL PLoS ONE 14:e0211966-e0211966(2019). RN [18] RP FUNCTION, AND INTERACTION WITH ITGAV:ITGB3. RX PubMed=18317590; DOI=10.1172/jci33374; RA Carneiro A.M., Cook E.H., Murphy D.L., Blakely R.D.; RT "Interactions between integrin alphaIIbbeta3 and the serotonin transporter RT regulate serotonin transport and platelet aggregation in mice and humans."; RL J. Clin. Invest. 118:1544-1552(2008). RN [19] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP MUTAGENESIS OF ASN-101 AND SER-336. RX PubMed=21730057; DOI=10.1074/jbc.m111.250308; RA Henry L.K., Iwamoto H., Field J.R., Kaufmann K., Dawson E.S., Jacobs M.T., RA Adams C., Felts B., Zdravkovic I., Armstrong V., Combs S., Solis E. Jr., RA Rudnick G., Noskov S.Y., DeFelice L.J., Meiler J., Blakely R.D.; RT "A conserved asparagine residue in transmembrane segment 1 (TM1) of RT serotonin transporter dictates chloride-coupled neurotransmitter RT transport."; RL J. Biol. Chem. 286:30823-30836(2011). RN [20] RP PHOSPHORYLATION AT TYR-47 AND TYR-142. RX PubMed=21992875; DOI=10.1124/mol.111.073171; RA Annamalai B., Mannangatti P., Arapulisamy O., Shippenberg T.S., RA Jayanthi L.D., Ramamoorthy S.; RT "Tyrosine phosphorylation of the human serotonin transporter: a role in the RT transporter stability and function."; RL Mol. Pharmacol. 81:73-85(2012). RN [21] RP FUNCTION, AND TRANSPORTER ACTIVITY. RX PubMed=27756841; DOI=10.1074/jbc.m116.753319; RA Hasenhuetl P.S., Freissmuth M., Sandtner W.; RT "Electrogenic Binding of Intracellular Cations Defines a Kinetic Decision RT Point in the Transport Cycle of the Human Serotonin Transporter."; RL J. Biol. Chem. 291:25864-25876(2016). RN [22] RP X-RAY CRYSTALLOGRAPHY (3.14 ANGSTROMS) OF 76-618 IN COMPLEXES WITH SODIUM RP IONS AND THE ANTIDEPRESSANTS CITALOPRAM AND PAROXETINE, FUNCTION, RP SUBCELLULAR LOCATION, TOPOLOGY, GLYCOSYLATION AT ASN-208 AND ASN-217, RP DISULFIDE BONDS, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=27049939; DOI=10.1038/nature17629; RA Coleman J.A., Green E.M., Gouaux E.; RT "X-ray structures and mechanism of the human serotonin transporter."; RL Nature 532:334-339(2016). RN [23] RP STRUCTURE BY ELECTRON MICROSCOPY (3.30 ANGSTROMS) OF 79-617 IN COMPLEX WITH RP SEROTONIN AND SODIUM IONS, FUNCTION, TRANSPORTER ACTIVITY, AND REACTION RP MECHANISM. RX PubMed=34851672; DOI=10.1126/sciadv.abl3857; RA Yang D., Gouaux E.; RT "Illumination of serotonin transporter mechanism and role of the allosteric RT site."; RL Sci. Adv. 7:eabl3857-eabl3857(2021). RN [24] RP VARIANTS ALA-56 AND ASN-605. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions of RT human genes."; RL Nat. Genet. 22:231-238(1999). RN [25] RP ERRATUM OF PUBMED:10391209. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [26] RP VARIANT VAL-425. RX PubMed=14593431; DOI=10.1038/sj.mp.4001365; RA Ozaki N., Goldman D., Kaye W.H., Plotnicov K., Greenberg B.D., RA Lappalainen J., Rudnick G., Murphy D.L.; RT "Serotonin transporter missense mutation associated with a complex RT neuropsychiatric phenotype."; RL Mol. Psychiatry 8:933-936(2003). RN [27] RP CHARACTERIZATION OF VARIANT VAL-425, FUNCTION, TRANSPORTER ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBCELLULAR LOCATION. RX PubMed=12869649; DOI=10.1124/mol.64.2.440; RA Kilic F., Murphy D.L., Rudnick G.; RT "A human serotonin transporter mutation causes constitutive activation of RT transport activity."; RL Mol. Pharmacol. 64:440-446(2003). RN [28] RP POLYMORPHISM IN THE PROMOTER REGION. RX PubMed=12869766; DOI=10.1126/science.1083968; RA Caspi A., Sugden K., Moffitt T.E., Taylor A., Craig I.W., Harrington H., RA McClay J., Mill J., Martin J., Braithwaite A., Poulton R.; RT "Influence of life stress on depression: moderation by a polymorphism in RT the 5-HTT gene."; RL Science 301:386-389(2003). RN [29] RP POLYMORPHISM IN THE PROMOTER REGION, AND INVOLVEMENT IN SUSCEPTIBILITY TO RP ANXIETY. RX PubMed=15108187; DOI=10.1002/ajmg.b.20158; RA Sen S., Burmeister M., Ghosh D.; RT "Meta-analysis of the association between a serotonin transporter promoter RT polymorphism (5-HTTLPR) and anxiety-related personality traits."; RL Am. J. Med. Genet. B Neuropsychiatr. Genet. 127B:85-89(2004). RN [30] RP INVOLVEMENT IN SUSCEPTIBILITY TO AUTISM, VARIANTS ALA-56; LEU-425; LEU-465 RP AND VAL-550, AND CHARACTERIZATION OF VARIANT ALA-56. RX PubMed=15995945; DOI=10.1086/432648; RA Sutcliffe J.S., Delahanty R.J., Prasad H.C., McCauley J.L., Han Q., RA Jiang L., Li C., Folstein S.E., Blakely R.D.; RT "Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers RT susceptibility to autism and rigid-compulsive behaviors."; RL Am. J. Hum. Genet. 77:265-279(2005). RN [31] RP INVOLVEMENT IN SUSCEPTIBILITY TO ALCOHOLISM. RX PubMed=15635638; DOI=10.1002/ajmg.b.30132; RA Feinn R., Nellissery M., Kranzler H.R.; RT "Meta-analysis of the association of a functional serotonin transporter RT promoter polymorphism with alcohol dependence."; RL Am. J. Med. Genet. B Neuropsychiatr. Genet. 133:79-84(2005). RN [32] RP INVOLVEMENT IN SUSCEPTIBILITY TO AUTISM, CHARACTERIZATION OF VARIANTS RP ALA-56; LEU-425; LEU-465 AND VAL-550, POLYMORPHISM, FUNCTION, AND RP TRANSPORTER ACTIVITY. RX PubMed=18957375; DOI=10.1098/rstb.2008.0143; RA Prasad H.C., Steiner J.A., Sutcliffe J.S., Blakely R.D.; RT "Enhanced activity of human serotonin transporter variants associated with RT autism."; RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 364:163-173(2009). RN [33] RP CHARACTERIZATION OF VARIANT ALA-56. RX PubMed=27111230; DOI=10.1172/jci84877; RA Margolis K.G., Li Z., Stevanovic K., Saurman V., Israelyan N., RA Anderson G.M., Snyder I., Veenstra-VanderWeele J., Blakely R.D., RA Gershon M.D.; RT "Serotonin transporter variant drives preventable gastrointestinal RT abnormalities in development and function."; RL J. Clin. Invest. 126:2221-2235(2016). CC -!- FUNCTION: Serotonin transporter that cotransports serotonin with one CC Na(+) ion in exchange for one K(+) ion and possibly one proton in an CC overall electroneutral transport cycle. Transports serotonin across the CC plasma membrane from the extracellular compartment to the cytosol thus CC limiting serotonin intercellular signaling (PubMed:27756841, CC PubMed:34851672, PubMed:21730057, PubMed:10407194, PubMed:27049939, CC PubMed:12869649). Essential for serotonin homeostasis in the central CC nervous system. In the developing somatosensory cortex, acts in CC glutamatergic neurons to control serotonin uptake and its trophic CC functions accounting for proper spatial organization of cortical CC neurons and elaboration of sensory circuits. In the mature cortex, acts CC primarily in brainstem raphe neurons to mediate serotonin uptake from CC the synaptic cleft back into the pre-synaptic terminal thus terminating CC serotonin signaling at the synapse (By similarity). Modulates mucosal CC serotonin levels in the gastrointestinal tract through uptake and CC clearance of serotonin in enterocytes. Required for enteric CC neurogenesis and gastrointestinal reflexes (By similarity). Regulates CC blood serotonin levels by ensuring rapid high affinity uptake of CC serotonin from plasma to platelets, where it is further stored in dense CC granules via vesicular monoamine transporters and then released upon CC stimulation (PubMed:17506858, PubMed:18317590). Mechanistically, the CC transport cycle starts with an outward-open conformation having Na1(+) CC and Cl(-) sites occupied. The binding of a second extracellular Na2(+) CC ion and serotonin substrate leads to structural changes to outward- CC occluded to inward-occluded to inward-open, where the Na2(+) ion and CC serotonin are released into the cytosol. Binding of intracellular K(+) CC ion induces conformational transitions to inward-occluded to outward- CC open and completes the cycle by releasing K(+) possibly together with a CC proton bound to Asp-98 into the extracellular compartment. Na1(+) and CC Cl(-) ions remain bound throughout the transport cycle CC (PubMed:27756841, PubMed:34851672, PubMed:21730057, PubMed:10407194, CC PubMed:27049939, PubMed:12869649). Additionally, displays serotonin- CC induced channel-like conductance for monovalent cations, mainly Na(+) CC ions. The channel activity is uncoupled from the transport cycle and CC may contribute to the membrane resting potential or excitability (By CC similarity). {ECO:0000250|UniProtKB:P31652, CC ECO:0000250|UniProtKB:Q60857, ECO:0000269|PubMed:10407194, CC ECO:0000269|PubMed:12869649, ECO:0000269|PubMed:17506858, CC ECO:0000269|PubMed:18317590, ECO:0000269|PubMed:21730057, CC ECO:0000269|PubMed:27049939, ECO:0000269|PubMed:27756841, CC ECO:0000269|PubMed:34851672}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) + K(+)(in) + Na(+)(out) + serotonin(out) = H(+)(out) CC + K(+)(out) + Na(+)(in) + serotonin(in); Xref=Rhea:RHEA:75839, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29101, ChEBI:CHEBI:29103, CC ChEBI:CHEBI:350546; Evidence={ECO:0000269|PubMed:10407194, CC ECO:0000269|PubMed:12869649, ECO:0000269|PubMed:21730057, CC ECO:0000269|PubMed:27049939, ECO:0000269|PubMed:27756841, CC ECO:0000269|PubMed:34851672}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75840; CC Evidence={ECO:0000305|PubMed:10407194, ECO:0000305|PubMed:12869649, CC ECO:0000305|PubMed:21730057, ECO:0000305|PubMed:27049939, CC ECO:0000305|PubMed:27756841, ECO:0000305|PubMed:34851672}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.28 uM for serotonin {ECO:0000269|PubMed:12869649}; CC KM=0.98 uM for serotonin {ECO:0000269|PubMed:17506858}; CC KM=0.28 uM for serotonin {ECO:0000269|PubMed:10407194}; CC KM=1.9 uM for serotonin {ECO:0000269|PubMed:27049939}; CC KM=0.9 uM for serotonin {ECO:0000269|PubMed:21730057}; CC Vmax=1.73 pmol/min/mg enzyme for serotonin CC {ECO:0000269|PubMed:12869649}; CC Vmax=1.58 pmol/min/mg enzyme for serotonin CC {ECO:0000269|PubMed:17506858}; CC Vmax=15 pmol/min/mg enzyme for serotonin CC {ECO:0000269|PubMed:10407194}; CC -!- SUBUNIT: Monomer or homooligomer (By similarity). Interacts with CC TGFB1I1 (PubMed:16803896). Interacts with SEC23A, SEC24C and PATJ. CC Interacts with NOS1; the interaction may diminish the cell surface CC localization of SERT in the brain and, correspondingly, reduce CC serotonin reuptake. Interacts with filamentous actin and STX1A (By CC similarity). Interacts (via the N-terminus) with STX1A (via the H3 CC domain); this interaction regulates SLC4A6 channel conductance (By CC similarity). Interacts (via C-terminus) with SCAMP2; the interaction is CC direct and retains transporter molecules intracellularly CC (PubMed:16870614). Interacts with ITGAV:ITGB3 (PubMed:18317590). CC Interacts (via C-terminus) with ITGB3; this interaction regulates CC SLC6A4 trafficking (PubMed:18317590). {ECO:0000250|UniProtKB:P31652, CC ECO:0000250|UniProtKB:Q60857, ECO:0000269|PubMed:16803896, CC ECO:0000269|PubMed:16870614, ECO:0000269|PubMed:18317590}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12869649, CC ECO:0000269|PubMed:16870614, ECO:0000269|PubMed:17506858, CC ECO:0000269|PubMed:27049939}; Multi-pass membrane protein CC {ECO:0000269|PubMed:27049939}. Endomembrane system CC {ECO:0000269|PubMed:16870614}; Multi-pass membrane protein CC {ECO:0000255}. Endosome membrane {ECO:0000269|PubMed:16870614}; Multi- CC pass membrane protein {ECO:0000255}. Synapse CC {ECO:0000250|UniProtKB:Q60857}. Cell junction, focal adhesion CC {ECO:0000250|UniProtKB:Q60857}. Cell projection, neuron projection CC {ECO:0000250|UniProtKB:Q60857}. Note=Could be part of recycling CC endosomes (PubMed:16870614). Density of transporter molecules on the CC plasma membrane is itself regulated by STX1A (By similarity). Density CC of transporter molecules on the plasma membrane is also regulated by CC serotonin (PubMed:17506858). Density of transporter molecules seems to CC be modulated by ITGAV:ITGB3 (By similarity). CC {ECO:0000250|UniProtKB:P31652, ECO:0000250|UniProtKB:Q60857, CC ECO:0000269|PubMed:16870614, ECO:0000269|PubMed:17506858}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P31645-1; Sequence=Displayed; CC Name=2; CC IsoId=P31645-2; Sequence=VSP_046553; CC -!- TISSUE SPECIFICITY: Expressed in platelets (at protein level). CC {ECO:0000269|PubMed:17506858}. CC -!- PTM: Phosphorylation at Thr-276 increases 5-HT uptake and is required CC for cGMP-mediated SERT regulation. {ECO:0000269|PubMed:17913921, CC ECO:0000269|PubMed:21992875}. CC -!- POLYMORPHISM: A polymorphism in the promoter region (5-HTT gene-linked CC polymorphic region, 5-HTTLPR) is located approximately 1 kb upstream of CC the transcription initiation site and is composed of 16 repeat CC elements. The polymorphism consists of a 44-bp insertion or deletion CC involving repeat elements 6 to 8. The short allele is associated with CC lower transcriptional efficiency of the promoter compared with the long CC allele. Over half of the Caucasian population has a short allele. CC Individuals with one or two copies of the short allele exhibit more CC depressive symptoms, diagnosable depression and suicidality in relation CC to stressful life events than individuals homozygous for the long CC allele. {ECO:0000269|PubMed:12869766}. CC -!- POLYMORPHISM: The 5-HTTLPR polymorphism may influence susceptibility to CC anxiety [MIM:607834]. {ECO:0000269|PubMed:15108187}. CC -!- POLYMORPHISM: The polymorphism Val-425 seems to be linked to a CC susceptibility to obsessive-compulsive disorder (OCD) [MIM:164230]. CC {ECO:0000269|PubMed:12869649, ECO:0000269|PubMed:14593431, CC ECO:0000269|PubMed:17913921}. CC -!- POLYMORPHISM: Genetic variations in SLC6A4 determine the genetic CC susceptibility to alcoholism [MIM:103780]. CC {ECO:0000269|PubMed:15635638}. CC -!- POLYMORPHISM: Polymorphisms that alter SLC6A4 expression or function CC may increase the susceptibility to autism. CC {ECO:0000269|PubMed:15995945, ECO:0000269|PubMed:18957375}. CC -!- MISCELLANEOUS: This protein is the target of psychomotor stimulants CC such as amphetamines or cocaine. CC -!- SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) CC (TC 2.A.22) family. SLC6A4 subfamily. {ECO:0000305}. CC -!- CAUTION: Was reported to interact with VIM, however the paper was CC retracted as some results and conclusions are not reliable. CC {ECO:0000269|PubMed:19270731, ECO:0000305|PubMed:30707744}. CC -!- CAUTION: Was reported to interact with RAB4 and to be induced by CC serotonin, however the paper was retracted as some results and CC conclusions are not reliable. {ECO:0000269|PubMed:18227069, CC ECO:0000305|PubMed:31201246}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Serotonin transporter entry; CC URL="https://en.wikipedia.org/wiki/Serotonin_transporter"; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Love, love, love... -Issue CC 123 of November 2010; CC URL="https://web.expasy.org/spotlight/back_issues/123"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/slc6a4/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X70697; CAA50029.1; -; mRNA. DR EMBL; L05568; AAA35492.1; -; mRNA. DR EMBL; AY902473; AAW80933.1; -; mRNA. DR EMBL; EU099989; ABV02581.1; -; Genomic_DNA. DR EMBL; BC069484; AAH69484.1; -; mRNA. DR EMBL; U79746; AAB93475.1; -; Genomic_DNA. DR EMBL; AK308014; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS11256.1; -. [P31645-1] DR PIR; A47398; A47398. DR RefSeq; NP_001036.1; NM_001045.5. [P31645-1] DR PDB; 5I6X; X-ray; 3.14 A; A=76-618. DR PDB; 5I6Z; X-ray; 4.53 A; A=76-618. DR PDB; 5I71; X-ray; 3.15 A; A=76-618. DR PDB; 5I73; X-ray; 3.24 A; A=76-618. DR PDB; 5I74; X-ray; 3.40 A; A=76-618. DR PDB; 5I75; X-ray; 3.49 A; A=76-618. DR PDB; 6AWN; X-ray; 3.62 A; A=76-618. DR PDB; 6AWO; X-ray; 3.53 A; A=76-618. DR PDB; 6AWP; X-ray; 3.80 A; A=76-618. DR PDB; 6AWQ; X-ray; 4.05 A; A=76-618. DR PDB; 6DZV; EM; 4.20 A; A=79-615. DR PDB; 6DZW; EM; 4.30 A; A=79-615. DR PDB; 6DZY; EM; 4.10 A; A=79-615. DR PDB; 6DZZ; EM; 3.60 A; A=78-617. DR PDB; 6VRH; EM; 3.30 A; A=1-630. DR PDB; 6VRK; EM; 4.10 A; A=1-630. DR PDB; 6VRL; EM; 3.80 A; A=1-630. DR PDB; 6W2B; X-ray; 4.70 A; A=76-618. DR PDB; 6W2C; X-ray; 6.30 A; A=76-618. DR PDB; 7LI6; EM; 3.50 A; A=79-617. DR PDB; 7LI7; EM; 4.10 A; A=79-615. DR PDB; 7LI8; EM; 3.90 A; A=79-617. DR PDB; 7LI9; EM; 3.90 A; A=79-617. DR PDB; 7LIA; EM; 3.30 A; A=79-617. DR PDB; 7LWD; EM; 3.65 A; A=77-617. DR PDB; 7MGW; EM; 3.50 A; A=79-615. DR PDB; 7TXT; EM; 3.00 A; S=77-617. DR PDBsum; 5I6X; -. DR PDBsum; 5I6Z; -. DR PDBsum; 5I71; -. DR PDBsum; 5I73; -. DR PDBsum; 5I74; -. DR PDBsum; 5I75; -. DR PDBsum; 6AWN; -. DR PDBsum; 6AWO; -. DR PDBsum; 6AWP; -. DR PDBsum; 6AWQ; -. DR PDBsum; 6DZV; -. DR PDBsum; 6DZW; -. DR PDBsum; 6DZY; -. DR PDBsum; 6DZZ; -. DR PDBsum; 6VRH; -. DR PDBsum; 6VRK; -. DR PDBsum; 6VRL; -. DR PDBsum; 6W2B; -. DR PDBsum; 6W2C; -. DR PDBsum; 7LI6; -. DR PDBsum; 7LI7; -. DR PDBsum; 7LI8; -. DR PDBsum; 7LI9; -. DR PDBsum; 7LIA; -. DR PDBsum; 7LWD; -. DR PDBsum; 7MGW; -. DR PDBsum; 7TXT; -. DR AlphaFoldDB; P31645; -. DR EMDB; EMD-21368; -. DR EMDB; EMD-21369; -. DR EMDB; EMD-21370; -. DR EMDB; EMD-23361; -. DR EMDB; EMD-23362; -. DR EMDB; EMD-23363; -. DR EMDB; EMD-23364; -. DR EMDB; EMD-23365; -. DR EMDB; EMD-23545; -. DR EMDB; EMD-23830; -. DR EMDB; EMD-26160; -. DR EMDB; EMD-8940; -. DR EMDB; EMD-8941; -. DR EMDB; EMD-8942; -. DR EMDB; EMD-8943; -. DR SMR; P31645; -. DR BioGRID; 112423; 23. DR IntAct; P31645; 3. DR MINT; P31645; -. DR STRING; 9606.ENSP00000261707; -. DR BindingDB; P31645; -. DR ChEMBL; CHEMBL228; -. DR DrugBank; DB01472; 4-Methoxyamphetamine. DR DrugBank; DB04836; Amineptine. DR DrugBank; DB05964; Amitifadine. DR DrugBank; DB00321; Amitriptyline. DR DrugBank; DB00543; Amoxapine. DR DrugBank; DB00182; Amphetamine. DR DrugBank; DB01238; Aripiprazole. DR DrugBank; DB00289; Atomoxetine. DR DrugBank; DB00245; Benzatropine. DR DrugBank; DB04889; Bicifadine. DR DrugBank; DB09016; Butriptyline. DR DrugBank; DB01114; Chlorpheniramine. DR DrugBank; DB00215; Citalopram. DR DrugBank; DB01242; Clomipramine. DR DrugBank; DB00907; Cocaine. DR DrugBank; DB05688; CRx-119. DR DrugBank; DB00924; Cyclobenzaprine. DR DrugBank; DB12305; Dasotraline. DR DrugBank; DB01151; Desipramine. DR DrugBank; DB06700; Desvenlafaxine. DR DrugBank; DB01191; Dexfenfluramine. DR DrugBank; DB06701; Dexmethylphenidate. DR DrugBank; DB00514; Dextromethorphan. DR DrugBank; DB00988; Dopamine. DR DrugBank; DB09167; Dosulepin. DR DrugBank; DB01142; Doxepin. DR DrugBank; DB00476; Duloxetine. DR DrugBank; DB01363; Ephedra sinica root. DR DrugBank; DB01175; Escitalopram. DR DrugBank; DB09194; Etoperidone. DR DrugBank; DB00574; Fenfluramine. DR DrugBank; DB00472; Fluoxetine. DR DrugBank; DB00176; Fluvoxamine. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB08918; Levomilnacipran. DR DrugBank; DB09195; Lorpiprazole. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB06077; Lumateperone. DR DrugBank; DB00579; Mazindol. DR DrugBank; DB00454; Meperidine. DR DrugBank; DB01577; Metamfetamine. DR DrugBank; DB06148; Mianserin. DR DrugBank; DB01454; Midomafetamine. DR DrugBank; DB04896; Milnacipran. DR DrugBank; DB00805; Minaprine. DR DrugBank; DB00370; Mirtazapine. DR DrugBank; DB01442; MMDA. DR DrugBank; DB01149; Nefazodone. DR DrugBank; DB09186; Nisoxetine. DR DrugBank; DB04821; Nomifensine. DR DrugBank; DB00540; Nortriptyline. DR DrugBank; DB05422; OPC-14523. DR DrugBank; DB00715; Paroxetine. DR DrugBank; DB00191; Phentermine. DR DrugBank; DB00721; Procaine. DR DrugBank; DB00344; Protriptyline. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB08839; Serotonin. DR DrugBank; DB01104; Sertraline. DR DrugBank; DB01105; Sibutramine. DR DrugBank; DB06204; Tapentadol. DR DrugBank; DB01079; Tegaserod. DR DrugBank; DB06156; Tesofensine. DR DrugBank; DB00193; Tramadol. DR DrugBank; DB00656; Trazodone. DR DrugBank; DB00726; Trimipramine. DR DrugBank; DB00285; Venlafaxine. DR DrugBank; DB00661; Verapamil. DR DrugBank; DB06684; Vilazodone. DR DrugBank; DB09068; Vortioxetine. DR DrugBank; DB04832; Zimelidine. DR DrugBank; DB09225; Zotepine. DR DrugCentral; P31645; -. DR GuidetoPHARMACOLOGY; 928; -. DR TCDB; 2.A.22.1.1; the neurotransmitter:sodium symporter (nss) family. DR GlyCosmos; P31645; 2 sites, No reported glycans. DR GlyGen; P31645; 2 sites. DR iPTMnet; P31645; -. DR PhosphoSitePlus; P31645; -. DR SwissPalm; P31645; -. DR BioMuta; SLC6A4; -. DR DMDM; 400630; -. DR MassIVE; P31645; -. DR PaxDb; 9606-ENSP00000261707; -. DR PeptideAtlas; P31645; -. DR ProteomicsDB; 54798; -. [P31645-1] DR ABCD; P31645; 2 sequenced antibodies. DR Antibodypedia; 26840; 399 antibodies from 36 providers. DR DNASU; 6532; -. DR Ensembl; ENST00000261707.7; ENSP00000261707.3; ENSG00000108576.10. [P31645-1] DR Ensembl; ENST00000401766.6; ENSP00000385822.2; ENSG00000108576.10. [P31645-1] DR Ensembl; ENST00000650711.1; ENSP00000498537.1; ENSG00000108576.10. [P31645-1] DR GeneID; 6532; -. DR KEGG; hsa:6532; -. DR MANE-Select; ENST00000650711.1; ENSP00000498537.1; NM_001045.6; NP_001036.1. DR UCSC; uc002hey.6; human. [P31645-1] DR AGR; HGNC:11050; -. DR CTD; 6532; -. DR DisGeNET; 6532; -. DR GeneCards; SLC6A4; -. DR HGNC; HGNC:11050; SLC6A4. DR HPA; ENSG00000108576; Group enriched (intestine, lung, placenta). DR MalaCards; SLC6A4; -. DR MIM; 103780; phenotype. DR MIM; 164230; phenotype. DR MIM; 182138; gene. DR MIM; 607834; phenotype. DR neXtProt; NX_P31645; -. DR OpenTargets; ENSG00000108576; -. DR PharmGKB; PA312; -. DR VEuPathDB; HostDB:ENSG00000108576; -. DR eggNOG; KOG3659; Eukaryota. DR GeneTree; ENSGT00940000157855; -. DR InParanoid; P31645; -. DR OMA; GEDCQGN; -. DR OrthoDB; 3084493at2759; -. DR PhylomeDB; P31645; -. DR TreeFam; TF343812; -. DR PathwayCommons; P31645; -. DR Reactome; R-HSA-380615; Serotonin clearance from the synaptic cleft. DR SignaLink; P31645; -. DR SIGNOR; P31645; -. DR BioGRID-ORCS; 6532; 15 hits in 1162 CRISPR screens. DR GeneWiki; Serotonin_transporter; -. DR GenomeRNAi; 6532; -. DR Pharos; P31645; Tclin. DR PRO; PR:P31645; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P31645; Protein. DR Bgee; ENSG00000108576; Expressed in right lung and 112 other cell types or tissues. DR ExpressionAtlas; P31645; baseline and differential. DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB. DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005925; C:focal adhesion; ISS:UniProtKB. DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0045211; C:postsynaptic membrane; IEA:Ensembl. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. DR GO; GO:0099154; C:serotonergic synapse; IEA:Ensembl. DR GO; GO:0045202; C:synapse; ISS:UniProtKB. DR GO; GO:0051015; F:actin filament binding; ISS:UniProtKB. DR GO; GO:0015297; F:antiporter activity; IDA:UniProtKB. DR GO; GO:0019811; F:cocaine binding; IEA:Ensembl. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0005178; F:integrin binding; IDA:UniProtKB. DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IDA:MGI. DR GO; GO:0005261; F:monoatomic cation channel activity; ISS:UniProtKB. DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; ISS:ARUK-UCL. DR GO; GO:0050998; F:nitric-oxide synthase binding; IEA:Ensembl. DR GO; GO:0051378; F:serotonin binding; IDA:UniProtKB. DR GO; GO:0005335; F:serotonin:sodium:chloride symporter activity; IDA:UniProtKB. DR GO; GO:0031402; F:sodium ion binding; IDA:UniProtKB. DR GO; GO:0017075; F:syntaxin-1 binding; IEA:Ensembl. DR GO; GO:0048854; P:brain morphogenesis; ISS:BHF-UCL. DR GO; GO:0071321; P:cellular response to cGMP; IEA:Ensembl. DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0048484; P:enteric nervous system development; IEA:Ensembl. DR GO; GO:0051899; P:membrane depolarization; ISS:UniProtKB. DR GO; GO:0007613; P:memory; IEA:Ensembl. DR GO; GO:0015844; P:monoamine transport; IDA:MGI. DR GO; GO:0021941; P:negative regulation of cerebellar granule cell precursor proliferation; IEA:Ensembl. DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl. DR GO; GO:0046621; P:negative regulation of organ growth; ISS:BHF-UCL. DR GO; GO:0032227; P:negative regulation of synaptic transmission, dopaminergic; IEA:Ensembl. DR GO; GO:0006836; P:neurotransmitter transport; ISS:ARUK-UCL. DR GO; GO:0070527; P:platelet aggregation; ISS:UniProtKB. DR GO; GO:0045787; P:positive regulation of cell cycle; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl. DR GO; GO:0014064; P:positive regulation of serotonin secretion; IEA:Ensembl. DR GO; GO:0090067; P:regulation of thalamus size; IMP:UniProtKB. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl. DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl. DR GO; GO:0009636; P:response to toxic substance; IDA:UniProtKB. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0051610; P:serotonin uptake; IDA:UniProtKB. DR GO; GO:0035176; P:social behavior; ISS:BHF-UCL. DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central. DR GO; GO:0042713; P:sperm ejaculation; IEA:Ensembl. DR GO; GO:0042310; P:vasoconstriction; IEA:Ensembl. DR CDD; cd11513; SLC6sbd_SERT; 1. DR InterPro; IPR000175; Na/ntran_symport. DR InterPro; IPR013086; Na/ntran_symport_serotonin_N. DR InterPro; IPR037272; SNS_sf. DR NCBIfam; NF037979; Na_transp; 1. DR PANTHER; PTHR11616:SF105; SODIUM-DEPENDENT SEROTONIN TRANSPORTER; 1. DR PANTHER; PTHR11616; SODIUM/CHLORIDE DEPENDENT TRANSPORTER; 1. DR Pfam; PF03491; 5HT_transport_N; 1. DR Pfam; PF00209; SNF; 1. DR PRINTS; PR01203; 5HTTRANSPORT. DR PRINTS; PR00176; NANEUSMPORT. DR SUPFAM; SSF161070; SNF-like; 1. DR PROSITE; PS00610; NA_NEUROTRAN_SYMP_1; 1. DR PROSITE; PS00754; NA_NEUROTRAN_SYMP_2; 1. DR PROSITE; PS50267; NA_NEUROTRAN_SYMP_3; 1. DR Genevisible; P31645; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Antiport; Cell junction; Cell membrane; KW Cell projection; Disulfide bond; Endosome; Glycoprotein; Membrane; KW Metal-binding; Neurotransmitter transport; Phosphoprotein; KW Reference proteome; Sodium; Synapse; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..630 FT /note="Sodium-dependent serotonin transporter" FT /id="PRO_0000214757" FT TOPO_DOM 1..87 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 88..112 FT /note="Helical; Name=1" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 113..115 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 116..135 FT /note="Helical; Name=2" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 136..160 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 161..186 FT /note="Helical; Name=3" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 187..252 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 253..271 FT /note="Helical; Name=4" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 272..277 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 278..297 FT /note="Helical; Name=5" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 298..324 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 325..347 FT /note="Helical; Name=6" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 348..360 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 361..380 FT /note="Helical; Name=7" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 381..421 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 422..443 FT /note="Helical; Name=8" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 444..463 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 464..483 FT /note="Helical; Name=9" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 484..494 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 495..516 FT /note="Helical; Name=10" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 517..538 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 539..558 FT /note="Helical; Name=11" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 559..574 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 575..595 FT /note="Helical; Name=12" FT /evidence="ECO:0000269|PubMed:27049939" FT TOPO_DOM 596..630 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT REGION 1..59 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 616..624 FT /note="Interaction with RAB4A" FT COMPBIAS 1..15 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 94 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6, FT ECO:0000269|PubMed:34851672, ECO:0000312|PDB:7LIA" FT BINDING 96 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000305|PubMed:27049939, ECO:0000312|PDB:7LIA, FT ECO:0007744|PDB:5I6X" FT BINDING 97 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6, FT ECO:0000269|PubMed:34851672, ECO:0000312|PDB:7LIA" FT BINDING 98 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7LIA" FT BINDING 98 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7MGW" FT BINDING 101 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:27049939, FT ECO:0007744|PDB:5I6X" FT BINDING 336 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000305|PubMed:27049939, ECO:0000312|PDB:7LIA, FT ECO:0007744|PDB:5I6X" FT BINDING 368 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000305|PubMed:27049939, FT ECO:0007744|PDB:5I6X" FT BINDING 434 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 437 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6, FT ECO:0000269|PubMed:34851672, ECO:0000312|PDB:7LIA" FT BINDING 438 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 439 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7LIA, ECO:0000312|PDB:7MGW" FT BINDING 494 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7MGW" FT BINDING 495 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7LIA" FT BINDING 556 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7LIA, ECO:0000312|PDB:7MGW" FT BINDING 559 FT /ligand="serotonin" FT /ligand_id="ChEBI:CHEBI:350546" FT /evidence="ECO:0000269|PubMed:34851672, FT ECO:0000312|PDB:7LIA, ECO:0000312|PDB:7MGW" FT MOD_RES 47 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:21992875" FT MOD_RES 142 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:21992875" FT MOD_RES 276 FT /note="Phosphothreonine; by PKG" FT /evidence="ECO:0000269|PubMed:17913921" FT CARBOHYD 208 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:27049939" FT CARBOHYD 217 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:27049939" FT DISULFID 200..209 FT /evidence="ECO:0007744|PDB:5I6X, ECO:0007744|PDB:5I6Z, FT ECO:0007744|PDB:5I71, ECO:0007744|PDB:5I73, FT ECO:0007744|PDB:5I74, ECO:0007744|PDB:5I75" FT VAR_SEQ 1 FT /note="M -> MSQSRRVNPDDRELGGDLQIQAPRDQLGSLADGHQCHLLTSRM (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_046553" FT VARIANT 56 FT /note="G -> A (found in 15 autistic individuals, decreased FT expression at the cell surface; increased affinity for FT serotonin; increased serotonin transport capacity; loss of FT regulation through cGMP and MAP kinases pathways; FT hypoplasia of the enteric nervous system and decreased FT gastrointestinal peristaltic reflexes shown by a mouse FT knockin model of the mutation; dbSNP:rs6355)" FT /evidence="ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:15995945, ECO:0000269|PubMed:18957375, FT ECO:0000269|PubMed:27111230" FT /id="VAR_014181" FT VARIANT 201 FT /note="K -> N (in dbSNP:rs2228673)" FT /id="VAR_029158" FT VARIANT 425 FT /note="I -> L (found in 2 autistic individuals; increased FT affinity for serotonin; increased serotonin transport rate; FT dbSNP:rs28914832)" FT /evidence="ECO:0000269|PubMed:15995945, FT ECO:0000269|PubMed:18957375" FT /id="VAR_036788" FT VARIANT 425 FT /note="I -> V (linked with susceptibility to FT obsessive-compulsive disorder; increased serotonin FT transport capacity; dbSNP:rs28914832)" FT /evidence="ECO:0000269|PubMed:12869649, FT ECO:0000269|PubMed:14593431, ECO:0000269|PubMed:17913921" FT /id="VAR_026751" FT VARIANT 465 FT /note="F -> L (found in 2 autistic individuals; increased FT expression at the cell surface; increased affinity for FT serotonin; dbSNP:rs28914833)" FT /evidence="ECO:0000269|PubMed:15995945, FT ECO:0000269|PubMed:18957375" FT /id="VAR_036789" FT VARIANT 550 FT /note="L -> V (found in 2 autistic individuals; increased FT expression at the cell surface; increased affinity for FT serotonin; dbSNP:rs28914834)" FT /evidence="ECO:0000269|PubMed:15995945, FT ECO:0000269|PubMed:18957375" FT /id="VAR_036790" FT VARIANT 605 FT /note="K -> N (in dbSNP:rs6352)" FT /evidence="ECO:0000269|PubMed:10391209" FT /id="VAR_014182" FT MUTAGEN 101 FT /note="N->A,C: Disrupts chloride ion dependence of FT serotonin transport. Results in larger serotonin-induced FT currents independent of the chloride ion gradient. FT Increases serotonin transport rate; when associated with FT C-336. Decreases expression at the cell surface." FT /evidence="ECO:0000269|PubMed:21730057" FT MUTAGEN 336 FT /note="S->C: Impairs serotonin transport. Results in FT chloride ion-independent serotonin transport; when FT associated with A-101 or C-101." FT /evidence="ECO:0000269|PubMed:21730057" FT HELIX 85..96 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 99..111 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 114..117 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 118..127 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 129..143 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 149..152 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 156..159 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 160..173 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 176..188 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 189..191 FT /evidence="ECO:0007829|PDB:5I74" FT STRAND 192..194 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 196..198 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 202..204 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 207..209 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 212..214 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 227..234 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 235..237 FT /evidence="ECO:0007829|PDB:5I74" FT HELIX 239..241 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 244..247 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 253..270 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 274..284 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 287..300 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 303..305 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 306..313 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 317..321 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 323..337 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:5I71" FT HELIX 343..349 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 353..355 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 358..389 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 396..398 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 403..407 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 409..415 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 417..419 FT /evidence="ECO:0007829|PDB:6VRH" FT HELIX 420..453 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 455..457 FT /evidence="ECO:0007829|PDB:6VRH" FT STRAND 458..460 FT /evidence="ECO:0007829|PDB:6VRH" FT HELIX 462..477 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 478..480 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 485..494 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 497..513 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 514..517 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 518..528 FT /evidence="ECO:0007829|PDB:5I6X" FT STRAND 529..531 FT /evidence="ECO:0007829|PDB:5I73" FT HELIX 535..542 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 544..558 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 574..583 FT /evidence="ECO:0007829|PDB:5I6X" FT TURN 584..587 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 588..599 FT /evidence="ECO:0007829|PDB:5I6X" FT HELIX 604..612 FT /evidence="ECO:0007829|PDB:5I6X" SQ SEQUENCE 630 AA; 70325 MW; 0EB535B0A579BDA2 CRC64; METTPLNSQK QLSACEDGED CQENGVLQKV VPTPGDKVES GQISNGYSAV PSPGAGDDTR HSIPATTTTL VAELHQGERE TWGKKVDFLL SVIGYAVDLG NVWRFPYICY QNGGGAFLLP YTIMAIFGGI PLFYMELALG QYHRNGCISI WRKICPIFKG IGYAICIIAF YIASYYNTIM AWALYYLISS FTDQLPWTSC KNSWNTGNCT NYFSEDNITW TLHSTSPAEE FYTRHVLQIH RSKGLQDLGG ISWQLALCIM LIFTVIYFSI WKGVKTSGKV VWVTATFPYI ILSVLLVRGA TLPGAWRGVL FYLKPNWQKL LETGVWIDAA AQIFFSLGPG FGVLLAFASY NKFNNNCYQD ALVTSVVNCM TSFVSGFVIF TVLGYMAEMR NEDVSEVAKD AGPSLLFITY AEAIANMPAS TFFAIIFFLM LITLGLDSTF AGLEGVITAV LDEFPHVWAK RRERFVLAVV ITCFFGSLVT LTFGGAYVVK LLEEYATGPA VLTVALIEAV AVSWFYGITQ FCRDVKEMLG FSPGWFWRIC WVAISPLFLL FIICSFLMSP PQLRLFQYNY PYWSIILGYC IGTSSFICIP TYIAYRLIIT PGTFKERIIK SITPETPTEI PCGDIRLNAV //