ID SC6A5_HUMAN Reviewed; 797 AA. AC Q9Y345; O95288; Q4VAM7; Q9BX77; DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 02-DEC-2020, entry version 176. DE RecName: Full=Sodium- and chloride-dependent glycine transporter 2; DE Short=GlyT-2; DE Short=GlyT2; DE AltName: Full=Solute carrier family 6 member 5; GN Name=SLC6A5; Synonyms=GLYT2, NET1; 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], FUNCTION, SUBCELLULAR LOCATION, AND VARIANTS RP SER-124 AND GLY-162. RX PubMed=9845349; DOI=10.1016/s0014-5793(98)01390-8; RA Morrow J.A., Collie I.T., Dunbar D.R., Walker G.B., Shahid M., Hill D.R.; RT "Molecular cloning and functional expression of the human glycine RT transporter GlyT2 and chromosomal localisation of the gene in the human RT genome."; RL FEBS Lett. 439:334-340(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND VARIANTS RP SER-102; SER-124 AND GLY-162. RC TISSUE=Spinal cord; RX PubMed=10381548; DOI=10.1016/s0169-328x(99)00135-7; RA Gallagher M.J., Burgess L.H., Brunden K.R.; RT "Characterization of multiple forms of the human glycine transporter type- RT 2."; RL Brain Res. Mol. Brain Res. 70:101-115(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND VARIANTS RP SER-124; GLY-162; ARG-184; ASN-463 AND ALA-751. RC TISSUE=Spinal cord; RX PubMed=10606742; DOI=10.1016/s0014-5793(99)01636-1; RA Evans J., Herdon H., Cairns W., O'Brien E., Chapman C., Terrett J., RA Gloger I.; RT "Cloning, functional characterisation and population analysis of a variant RT form of the human glycine type 2 transporter."; RL FEBS Lett. 463:301-306(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS SER-124 AND GLY-162. RA Luyten W.; RT "Cloning and expression of a human glycine transporter type II."; RL Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS SER-124 AND GLY-162. 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 VARIANTS HKPX3 VAL-306; MET-425; CYS-482; CYS-491; SER-509 AND ARG-510, RP VARIANT GLU-89, CHARACTERIZATION OF VARIANTS HKPX3 VAL-306; MET-425; RP CYS-482; CYS-491; SER-509 AND ARG-510, AND CHARACTERIZATION OF VARIANT RP GLU-89. RX PubMed=16751771; DOI=10.1038/ng1814; RA Rees M.I., Harvey K., Pearce B.R., Chung S.K., Duguid I.C., Thomas P., RA Beatty S., Graham G.E., Armstrong L., Shiang R., Abbott K.J., Zuberi S.M., RA Stephenson J.B., Owen M.J., Tijssen M.A., van den Maagdenberg A.M., RA Smart T.G., Supplisson S., Harvey R.J.; RT "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic RT component of human startle disease."; RL Nat. Genet. 38:801-806(2006). RN [8] RP VARIANT [LARGE SCALE ANALYSIS] GLU-632. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [9] RP VARIANT HKPX3 LEU-429, CHARACTERIZATION OF VARIANT HKPX3 LEU-429, FUNCTION, RP SUBCELLULAR LOCATION, AND GLYCOSYLATION. RX PubMed=31370103; DOI=10.1111/ejn.14533; RA Kitzenmaier A., Schaefer N., Kasaragod V.B., Polster T., Hantschmann R., RA Schindelin H., Villmann C.; RT "The P429L loss of function mutation of the human glycine transporter 2 RT associated with hyperekplexia."; RL Eur. J. Neurosci. 0:0-0(2019). CC -!- FUNCTION: Sodium- and chloride-dependent glycine transporter CC (PubMed:9845349, PubMed:10381548, PubMed:10606742, PubMed:31370103). CC Terminates the action of glycine by its high affinity sodium-dependent CC reuptake into presynaptic terminals (PubMed:9845349). May be CC responsible for the termination of neurotransmission at strychnine- CC sensitive glycinergic synapses (PubMed:9845349). CC {ECO:0000269|PubMed:10381548, ECO:0000269|PubMed:10606742, CC ECO:0000269|PubMed:31370103, ECO:0000269|PubMed:9845349}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10381548, CC ECO:0000269|PubMed:10606742, ECO:0000269|PubMed:31370103, CC ECO:0000269|PubMed:9845349}; Multi-pass membrane protein {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Expressed in medulla, and to a lesser extent in CC spinal cord and cerebellum. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:31370103}. CC -!- DISEASE: Hyperekplexia 3 (HKPX3) [MIM:614618]: A neurologic disorder CC characterized by neonatal hypertonia, an exaggerated startle response CC to tactile or acoustic stimuli, and life-threatening neonatal apnea CC episodes. Notably, in some cases, symptoms resolved in the first year CC of life. {ECO:0000269|PubMed:16751771, ECO:0000269|PubMed:31370103}. CC Note=The disease is caused by mutations affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) (TC CC 2.A.22) family. SLC6A5 subfamily. {ECO:0000305}. 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; AF085412; AAC95145.1; -; mRNA. DR EMBL; AF142501; AAD27892.1; -; mRNA. DR EMBL; AF352733; AAK29670.1; -; mRNA. DR EMBL; AF117999; AAK12641.1; -; mRNA. DR EMBL; AC090707; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC096319; AAH96319.1; -; mRNA. DR CCDS; CCDS7854.1; -. DR RefSeq; NP_001305298.1; NM_001318369.1. DR RefSeq; NP_004202.3; NM_004211.4. DR SMR; Q9Y345; -. DR BioGRID; 114599; 13. DR IntAct; Q9Y345; 10. DR STRING; 9606.ENSP00000434364; -. DR BindingDB; Q9Y345; -. DR ChEMBL; CHEMBL3060; -. DR DrugBank; DB00145; Glycine. DR DrugCentral; Q9Y345; -. DR GuidetoPHARMACOLOGY; 936; -. DR TCDB; 2.A.22.2.10; the neurotransmitter:sodium symporter (nss) family. DR GlyGen; Q9Y345; 4 sites. DR iPTMnet; Q9Y345; -. DR PhosphoSitePlus; Q9Y345; -. DR BioMuta; SLC6A5; -. DR DMDM; 296452967; -. DR MassIVE; Q9Y345; -. DR PaxDb; Q9Y345; -. DR PeptideAtlas; Q9Y345; -. DR PRIDE; Q9Y345; -. DR ProteomicsDB; 85975; -. DR Antibodypedia; 25288; 71 antibodies. DR Ensembl; ENST00000525748; ENSP00000434364; ENSG00000165970. DR GeneID; 9152; -. DR KEGG; hsa:9152; -. DR UCSC; uc001mqd.4; human. DR CTD; 9152; -. DR DisGeNET; 9152; -. DR EuPathDB; HostDB:ENSG00000165970.11; -. DR GeneCards; SLC6A5; -. DR GeneReviews; SLC6A5; -. DR HGNC; HGNC:11051; SLC6A5. DR HPA; ENSG00000165970; Tissue enriched (brain). DR MalaCards; SLC6A5; -. DR MIM; 604159; gene. DR MIM; 614618; phenotype. DR neXtProt; NX_Q9Y345; -. DR OpenTargets; ENSG00000165970; -. DR Orphanet; 3197; Hereditary hyperekplexia. DR PharmGKB; PA35911; -. DR eggNOG; KOG3660; Eukaryota. DR GeneTree; ENSGT00940000154963; -. DR HOGENOM; CLU_006855_4_0_1; -. DR InParanoid; Q9Y345; -. DR OMA; TYEDYTY; -. DR OrthoDB; 250396at2759; -. DR PhylomeDB; Q9Y345; -. DR TreeFam; TF343812; -. DR PathwayCommons; Q9Y345; -. DR Reactome; R-HSA-442660; Na+/Cl- dependent neurotransmitter transporters. DR Reactome; R-HSA-5619089; Defective SLC6A5 causes hyperekplexia 3 (HKPX3). DR BioGRID-ORCS; 9152; 4 hits in 843 CRISPR screens. DR ChiTaRS; SLC6A5; human. DR GeneWiki; Glycine_transporter_2; -. DR GenomeRNAi; 9152; -. DR Pharos; Q9Y345; Tchem. DR PRO; PR:Q9Y345; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q9Y345; protein. DR Bgee; ENSG00000165970; Expressed in secondary oocyte and 31 other tissues. DR ExpressionAtlas; Q9Y345; baseline and differential. DR Genevisible; Q9Y345; HS. DR GO; GO:0031045; C:dense core granule; ISS:ARUK-UCL. DR GO; GO:0005768; C:endosome; ISS:ARUK-UCL. DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IDA:FlyBase. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0015375; F:glycine:sodium symporter activity; IDA:FlyBase. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc. DR GO; GO:1903804; P:glycine import across plasma membrane; IDA:FlyBase. DR GO; GO:0001504; P:neurotransmitter uptake; IEA:Ensembl. DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central. DR GO; GO:0060012; P:synaptic transmission, glycinergic; IMP:FlyBase. DR InterPro; IPR000175; Na/ntran_symport. DR InterPro; IPR037272; SNS_sf. DR PANTHER; PTHR11616; PTHR11616; 1. DR Pfam; PF00209; SNF; 1. DR PRINTS; PR00176; NANEUSMPORT. DR SUPFAM; SSF161070; SSF161070; 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. PE 1: Evidence at protein level; KW Cell membrane; Disease mutation; Disulfide bond; Glycoprotein; Membrane; KW Metal-binding; Neurotransmitter transport; Phosphoprotein; Polymorphism; KW Reference proteome; Sodium; Symport; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..797 FT /note="Sodium- and chloride-dependent glycine transporter FT 2" FT /id="PRO_0000214762" FT TOPO_DOM 1..199 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 200..220 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TRANSMEM 228..247 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TRANSMEM 271..291 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 292..393 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 394..412 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TRANSMEM 421..438 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TRANSMEM 474..491 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TRANSMEM 503..524 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TRANSMEM 557..576 FT /note="Helical; Name=8" FT /evidence="ECO:0000255" FT TRANSMEM 604..622 FT /note="Helical; Name=9" FT /evidence="ECO:0000255" FT TRANSMEM 638..658 FT /note="Helical; Name=10" FT /evidence="ECO:0000255" FT TRANSMEM 679..698 FT /note="Helical; Name=11" FT /evidence="ECO:0000255" FT TRANSMEM 717..735 FT /note="Helical; Name=12" FT /evidence="ECO:0000255" FT TOPO_DOM 736..797 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT METAL 206 FT /note="Sodium 1; via carbonyl oxygen" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 208 FT /note="Sodium 2; via carbonyl oxygen" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 209 FT /note="Sodium 1; via carbonyl oxygen" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 213 FT /note="Sodium 2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 477 FT /note="Sodium 2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 509 FT /note="Sodium 2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 574 FT /note="Sodium 1; via carbonyl oxygen" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT METAL 577 FT /note="Sodium 1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT MOD_RES 56 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P58295" FT MOD_RES 57 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q761V0" FT MOD_RES 84 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q761V0" FT CARBOHYD 343 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 353 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 358 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 364 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 311..320 FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT VARIANT 89 FT /note="A -> E (no effect on subcellular location; no effect FT on glycine transport; dbSNP:rs61736602)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044163" FT VARIANT 102 FT /note="G -> S (in dbSNP:rs1443547)" FT /evidence="ECO:0000269|PubMed:10381548" FT /id="VAR_044164" FT VARIANT 124 FT /note="F -> S (in dbSNP:rs1443548)" FT /evidence="ECO:0000269|PubMed:10381548, FT ECO:0000269|PubMed:10606742, ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:9845349, ECO:0000269|Ref.4" FT /id="VAR_044165" FT VARIANT 132 FT /note="A -> G (in dbSNP:rs34243519)" FT /id="VAR_044166" FT VARIANT 162 FT /note="A -> G (in dbSNP:rs1443549)" FT /evidence="ECO:0000269|PubMed:10381548, FT ECO:0000269|PubMed:10606742, ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:9845349, ECO:0000269|Ref.4" FT /id="VAR_044167" FT VARIANT 184 FT /note="Q -> R" FT /evidence="ECO:0000269|PubMed:10606742" FT /id="VAR_011591" FT VARIANT 306 FT /note="L -> V (in HKPX3; compound heterozygote with S-509; FT impairment of glycine transport when coexpressed with S-509 FT in vitro; dbSNP:rs121908496)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044168" FT VARIANT 425 FT /note="T -> M (in HKPX3; no effect on subcellular location; FT impairs glycine transport; dbSNP:rs121908498)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044169" FT VARIANT 429 FT /note="P -> L (in HKPX3; impairs glycine transport; no FT effect on subcellular location; dbSNP:rs745539706)" FT /evidence="ECO:0000269|PubMed:31370103" FT /id="VAR_082588" FT VARIANT 457 FT /note="K -> N (in dbSNP:rs3740870)" FT /id="VAR_044170" FT VARIANT 463 FT /note="D -> N (in dbSNP:rs1805091)" FT /evidence="ECO:0000269|PubMed:10606742" FT /id="VAR_011592" FT VARIANT 482 FT /note="W -> C (in HKPX3; no effect on subcellular location; FT impairs glycine transport)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044171" FT VARIANT 491 FT /note="Y -> C (in HKPX3; no effect on subcellular location; FT impairs glycine transport; dbSNP:rs121908494)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044172" FT VARIANT 499 FT /note="Y -> F (in dbSNP:rs7944684)" FT /id="VAR_044173" FT VARIANT 509 FT /note="N -> S (in HKPX3; compound heterozygote with V-306; FT no effect on subcellular location; impairs glycine FT transport; dbSNP:rs121908497)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044174" FT VARIANT 510 FT /note="S -> R (in HKPX3; results in the formation of large FT aggregates in the cytoplasm; impairs glycine transport; FT dbSNP:rs281864926)" FT /evidence="ECO:0000269|PubMed:16751771" FT /id="VAR_044175" FT VARIANT 632 FT /note="V -> E (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036160" FT VARIANT 751 FT /note="V -> A" FT /evidence="ECO:0000269|PubMed:10606742" FT /id="VAR_011593" FT VARIANT 767 FT /note="G -> R (in dbSNP:rs16906628)" FT /id="VAR_044176" FT CONFLICT 24 FT /note="G -> S (in Ref. 2; AAD27892)" FT /evidence="ECO:0000305" FT CONFLICT 155 FT /note="S -> G (in Ref. 2; AAD27892)" FT /evidence="ECO:0000305" FT CONFLICT 188 FT /note="N -> D (in Ref. 2; AAD27892)" FT /evidence="ECO:0000305" FT CONFLICT 362 FT /note="Q -> L (in Ref. 2; AAD27892)" FT /evidence="ECO:0000305" FT CONFLICT 582 FT /note="T -> S (in Ref. 2; AAD27892)" FT /evidence="ECO:0000305" SQ SEQUENCE 797 AA; 87434 MW; 47D8A9B179896CE0 CRC64; MDCSAPKEMN KLPANSPEAA AAQGHPDGPC APRTSPEQEL PAAAAPPPPR VPRSASTGAQ TFQSADARAC EAERPGVGSC KLSSPRAQAA SAALRDLREA QGAQASPPPG SSGPGNALHC KIPFLRGPEG DANVSVGKGT LERNNTPVVG WVNMSQSTVV LATDGITSVL PGSVATVATQ EDEQGDENKA RGNWSSKLDF ILSMVGYAVG LGNVWRFPYL AFQNGGGAFL IPYLMMLALA GLPIFFLEVS LGQFASQGPV SVWKAIPALQ GCGIAMLIIS VLIAIYYNVI ICYTLFYLFA SFVSVLPWGS CNNPWNTPEC KDKTKLLLDS CVISDHPKIQ IKNSTFCMTA YPNVTMVNFT SQANKTFVSG SEEYFKYFVL KISAGIEYPG EIRWPLALCL FLAWVIVYAS LAKGIKTSGK VVYFTATFPY VVLVILLIRG VTLPGAGAGI WYFITPKWEK LTDATVWKDA ATQIFFSLSA AWGGLITLSS YNKFHNNCYR DTLIVTCTNS ATSIFAGFVI FSVIGFMANE RKVNIENVAD QGPGIAFVVY PEALTRLPLS PFWAIIFFLM LLTLGLDTMF ATIETIVTSI SDEFPKYLRT HKPVFTLGCC ICFFIMGFPM ITQGGIYMFQ LVDTYAASYA LVIIAIFELV GISYVYGLQR FCEDIEMMIG FQPNIFWKVC WAFVTPTILT FILCFSFYQW EPMTYGSYRY PNWSMVLGWL MLACSVIWIP IMFVIKMHLA PGRFIERLKL VCSPQPDWGP FLAQHRGERY KNMIDPLGTS SLGLKLPVKD LELGTQC //