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EAA4_HUMAN
ID   EAA4_HUMAN              Reviewed;         564 AA.
AC   P48664; Q8N753;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 1.
DT   03-AUG-2022, entry version 179.
DE   RecName: Full=Excitatory amino acid transporter 4;
DE   AltName: Full=Sodium-dependent glutamate/aspartate transporter;
DE   AltName: Full=Solute carrier family 1 member 6;
GN   Name=SLC1A6 {ECO:0000312|HGNC:HGNC:10944}; Synonyms=EAAT4;
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), FUNCTION, SUBCELLULAR LOCATION,
RP   TRANSPORTER ACTIVITY, TISSUE SPECIFICITY, AND BIOPHYSICOCHEMICAL
RP   PROPERTIES.
RC   TISSUE=Brain;
RX   PubMed=7791878; DOI=10.1038/375599a0;
RA   Fairman W.A., Vandenberg R.J., Arriza J.L., Kavanaugh M.P., Amara S.G.;
RT   "An excitatory amino-acid transporter with properties of a ligand-gated
RT   chloride channel.";
RL   Nature 375:599-603(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15057824; DOI=10.1038/nature02399;
RA   Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA   Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA   Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA   Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA   Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA   Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA   Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA   Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA   Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA   McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA   Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA   Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA   She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA   Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA   Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA   Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA   Rubin E.M., Lucas S.M.;
RT   "The DNA sequence and biology of human chromosome 19.";
RL   Nature 428:529-535(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Testis;
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   [4]
RP   FUNCTION, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP   TRANSPORTER ACTIVITY.
RX   PubMed=26690923; DOI=10.1007/s00232-015-9863-0;
RA   Abousaab A., Warsi J., Elvira B., Lang F.;
RT   "Caveolin-1 Sensitivity of Excitatory Amino Acid Transporters EAAT1, EAAT2,
RT   EAAT3, and EAAT4.";
RL   J. Membr. Biol. 249:239-249(2016).
CC   -!- FUNCTION: Sodium-dependent, high-affinity amino acid transporter that
CC       mediates the uptake of L-glutamate and also L-aspartate and D-aspartate
CC       (PubMed:7791878, PubMed:26690923). Functions as a symporter that
CC       transports one amino acid molecule together with two or three Na(+)
CC       ions and one proton, in parallel with the counter-transport of one K(+)
CC       ion. Mediates Cl(-) flux that is not coupled to amino acid transport;
CC       this avoids the accumulation of negative charges due to aspartate and
CC       Na(+) symport (PubMed:7791878). Plays a redundant role in the rapid
CC       removal of released glutamate from the synaptic cleft, which is
CC       essential for terminating the postsynaptic action of glutamate
CC       (Probable). {ECO:0000250|UniProtKB:O35921, ECO:0000269|PubMed:26690923,
CC       ECO:0000269|PubMed:7791878}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+)(out) + K(+)(in) + L-glutamate(out) + 3 Na(+)(out) =
CC         H(+)(in) + K(+)(out) + L-glutamate(in) + 3 Na(+)(in);
CC         Xref=Rhea:RHEA:70699, ChEBI:CHEBI:15378, ChEBI:CHEBI:29101,
CC         ChEBI:CHEBI:29103, ChEBI:CHEBI:29985;
CC         Evidence={ECO:0000269|PubMed:7791878};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H(+)(out) + K(+)(in) + L-aspartate(out) + 3 Na(+)(out) =
CC         H(+)(in) + K(+)(out) + L-aspartate(in) + 3 Na(+)(in);
CC         Xref=Rhea:RHEA:70851, ChEBI:CHEBI:15378, ChEBI:CHEBI:29101,
CC         ChEBI:CHEBI:29103, ChEBI:CHEBI:29991;
CC         Evidence={ECO:0000269|PubMed:7791878};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=D-aspartate(out) + H(+)(out) + K(+)(in) + 3 Na(+)(out) = D-
CC         aspartate(in) + H(+)(in) + K(+)(out) + 3 Na(+)(in);
CC         Xref=Rhea:RHEA:71379, ChEBI:CHEBI:15378, ChEBI:CHEBI:29101,
CC         ChEBI:CHEBI:29103, ChEBI:CHEBI:29990;
CC         Evidence={ECO:0000305|PubMed:7791878};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.94 uM for L-aspartate {ECO:0000269|PubMed:7791878};
CC         KM=2.5 uM for D-aspartate {ECO:0000269|PubMed:7791878};
CC         KM=168 uM for L-alfa-amino adipate {ECO:0000269|PubMed:7791878};
CC         KM=99 uM for L-quisqualate {ECO:0000269|PubMed:7791878};
CC         KM=403 uM for L-homocysteate {ECO:0000269|PubMed:7791878};
CC         KM=2.6 uM for L-trans-2,4-pyrrolidine dicarboxylic acid
CC         {ECO:0000269|PubMed:7791878};
CC         KM=2.49 uM for L-glutamate {ECO:0000269|PubMed:7791878};
CC   -!- SUBUNIT: Homotrimer. {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26690923,
CC       ECO:0000269|PubMed:7791878}; Multi-pass membrane protein {ECO:0000305}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P48664-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P48664-2; Sequence=VSP_055130;
CC   -!- TISSUE SPECIFICITY: Brain, mainly in the cerebellum (PubMed:7791878).
CC       Expressed densely and selectively in cell bodies of Purkinje cells.
CC       {ECO:0000269|PubMed:7791878}.
CC   -!- DOMAIN: Contains eight transmembrane regions plus two helical hairpins
CC       that dip into the membrane. These helical hairpin structures play an
CC       important role in the transport process. The first enters the membrane
CC       from the cytoplasmic side, the second one from the extracellular side.
CC       During the transport cycle, the regions involved in amino acid
CC       transport, and especially the helical hairpins, move vertically by
CC       about 15-18 Angstroms, alternating between exposure to the aqueous
CC       phase and reinsertion in the lipid bilayer. In contrast, the regions
CC       involved in trimerization do not move. {ECO:0000250|UniProtKB:P43003}.
CC   -!- SIMILARITY: Belongs to the dicarboxylate/amino acid:cation symporter
CC       (DAACS) (TC 2.A.23) family. SLC1A6 subfamily. {ECO:0000305}.
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DR   EMBL; U18244; AAA75314.1; -; mRNA.
DR   EMBL; AC004659; AAC15754.1; -; Genomic_DNA.
DR   EMBL; AC104528; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC028721; AAH28721.1; -; mRNA.
DR   EMBL; BC040604; AAH40604.1; -; mRNA.
DR   CCDS; CCDS12321.1; -. [P48664-1]
DR   CCDS; CCDS62578.1; -. [P48664-2]
DR   PIR; S58398; S58398.
DR   RefSeq; NP_001259016.1; NM_001272087.1. [P48664-2]
DR   RefSeq; NP_001259017.1; NM_001272088.1. [P48664-2]
DR   RefSeq; NP_005062.1; NM_005071.2. [P48664-1]
DR   RefSeq; XP_006722905.1; XM_006722842.1.
DR   RefSeq; XP_006722907.1; XM_006722844.1.
DR   RefSeq; XP_016882641.1; XM_017027152.1. [P48664-1]
DR   AlphaFoldDB; P48664; -.
DR   SMR; P48664; -.
DR   BioGRID; 112402; 2.
DR   IntAct; P48664; 1.
DR   STRING; 9606.ENSP00000221742; -.
DR   DrugBank; DB00142; Glutamic acid.
DR   GuidetoPHARMACOLOGY; 871; -.
DR   TCDB; 2.A.23.2.8; the dicarboxylate/amino acid:cation (na(+) or h(+)) symporter (daacs) family.
DR   GlyGen; P48664; 3 sites.
DR   iPTMnet; P48664; -.
DR   PhosphoSitePlus; P48664; -.
DR   BioMuta; SLC1A6; -.
DR   DMDM; 1352333; -.
DR   MassIVE; P48664; -.
DR   MaxQB; P48664; -.
DR   PaxDb; P48664; -.
DR   PeptideAtlas; P48664; -.
DR   PRIDE; P48664; -.
DR   ProteomicsDB; 55921; -. [P48664-1]
DR   ProteomicsDB; 72264; -.
DR   Antibodypedia; 26923; 190 antibodies from 25 providers.
DR   DNASU; 6511; -.
DR   Ensembl; ENST00000221742.7; ENSP00000221742.3; ENSG00000105143.13. [P48664-1]
DR   Ensembl; ENST00000544886.6; ENSP00000446175.1; ENSG00000105143.13. [P48664-2]
DR   Ensembl; ENST00000594383.2; ENSP00000472133.2; ENSG00000105143.13. [P48664-1]
DR   Ensembl; ENST00000598504.5; ENSP00000471781.1; ENSG00000105143.13. [P48664-2]
DR   GeneID; 6511; -.
DR   KEGG; hsa:6511; -.
DR   MANE-Select; ENST00000594383.2; ENSP00000472133.2; NM_005071.3; NP_005062.1.
DR   UCSC; uc002naa.3; human. [P48664-1]
DR   CTD; 6511; -.
DR   DisGeNET; 6511; -.
DR   GeneCards; SLC1A6; -.
DR   HGNC; HGNC:10944; SLC1A6.
DR   HPA; ENSG00000105143; Group enriched (brain, testis).
DR   MIM; 600637; gene.
DR   neXtProt; NX_P48664; -.
DR   OpenTargets; ENSG00000105143; -.
DR   PharmGKB; PA35831; -.
DR   VEuPathDB; HostDB:ENSG00000105143; -.
DR   eggNOG; KOG3787; Eukaryota.
DR   GeneTree; ENSGT00940000159972; -.
DR   HOGENOM; CLU_019375_3_2_1; -.
DR   InParanoid; P48664; -.
DR   OMA; AQIYGIP; -.
DR   OrthoDB; 1184392at2759; -.
DR   PhylomeDB; P48664; -.
DR   TreeFam; TF315206; -.
DR   PathwayCommons; P48664; -.
DR   Reactome; R-HSA-210500; Glutamate Neurotransmitter Release Cycle.
DR   Reactome; R-HSA-425393; Transport of inorganic cations/anions and amino acids/oligopeptides.
DR   SignaLink; P48664; -.
DR   SIGNOR; P48664; -.
DR   BioGRID-ORCS; 6511; 12 hits in 1072 CRISPR screens.
DR   ChiTaRS; SLC1A6; human.
DR   GeneWiki; Excitatory_amino-acid_transporter_4; -.
DR   GenomeRNAi; 6511; -.
DR   Pharos; P48664; Tchem.
DR   PRO; PR:P48664; -.
DR   Proteomes; UP000005640; Chromosome 19.
DR   RNAct; P48664; protein.
DR   Bgee; ENSG00000105143; Expressed in right hemisphere of cerebellum and 97 other tissues.
DR   ExpressionAtlas; P48664; baseline and differential.
DR   Genevisible; P48664; HS.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR   GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR   GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR   GO; GO:0045111; C:intermediate filament cytoskeleton; IDA:HPA.
DR   GO; GO:0016020; C:membrane; TAS:ProtInc.
DR   GO; GO:0098796; C:membrane protein complex; ISS:ARUK-UCL.
DR   GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR   GO; GO:0015501; F:glutamate:sodium symporter activity; IDA:UniProtKB.
DR   GO; GO:0005314; F:high-affinity L-glutamate transmembrane transporter activity; ISS:UniProtKB.
DR   GO; GO:0015183; F:L-aspartate transmembrane transporter activity; IDA:UniProtKB.
DR   GO; GO:0005313; F:L-glutamate transmembrane transporter activity; IDA:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0015175; F:neutral amino acid transmembrane transporter activity; IBA:GO_Central.
DR   GO; GO:0015810; P:aspartate transmembrane transport; TAS:ProtInc.
DR   GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR   GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR   GO; GO:0006811; P:ion transport; TAS:Reactome.
DR   GO; GO:0140009; P:L-aspartate import across plasma membrane; IDA:UniProtKB.
DR   GO; GO:0098712; P:L-glutamate import across plasma membrane; IDA:UniProtKB.
DR   GO; GO:0015813; P:L-glutamate transmembrane transport; IBA:GO_Central.
DR   GO; GO:0006836; P:neurotransmitter transport; TAS:Reactome.
DR   GO; GO:0001504; P:neurotransmitter uptake; IMP:SynGO.
DR   GO; GO:0042391; P:regulation of membrane potential; IEA:Ensembl.
DR   Gene3D; 1.10.3860.10; -; 1.
DR   InterPro; IPR001991; Na-dicarboxylate_symporter.
DR   InterPro; IPR018107; Na-dicarboxylate_symporter_CS.
DR   InterPro; IPR036458; Na:dicarbo_symporter_sf.
DR   Pfam; PF00375; SDF; 1.
DR   SUPFAM; SSF118215; SSF118215; 1.
DR   PROSITE; PS00713; NA_DICARBOXYL_SYMP_1; 1.
DR   PROSITE; PS00714; NA_DICARBOXYL_SYMP_2; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Amino-acid transport; Cell membrane; Chloride;
KW   Glycoprotein; Membrane; Metal-binding; Phosphoprotein; Potassium;
KW   Reference proteome; Sodium; Symport; Transmembrane; Transmembrane helix;
KW   Transport.
FT   CHAIN           1..564
FT                   /note="Excitatory amino acid transporter 4"
FT                   /id="PRO_0000202070"
FT   TOPO_DOM        1..55
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        56..76
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        99..119
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        133..153
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        262..285
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   TRANSMEM        295..322
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   TRANSMEM        344..365
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   INTRAMEM        371..401
FT                   /note="Discontinuously helical"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   TRANSMEM        411..437
FT                   /note="Helical; Name=7"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   INTRAMEM        451..484
FT                   /note="Discontinuously helical"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   TRANSMEM        498..519
FT                   /note="Helical; Name=8"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         388..390
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         419
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O59010"
FT   BINDING         421
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         423
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O59010"
FT   BINDING         427
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         468..472
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         501
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         508
FT                   /ligand="L-aspartate"
FT                   /ligand_id="ChEBI:CHEBI:29991"
FT                   /evidence="ECO:0000250|UniProtKB:P43003"
FT   BINDING         508
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O59010"
FT   BINDING         512
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O59010"
FT   MOD_RES         2
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O35921"
FT   CARBOHYD        216
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        232
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        239
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         313..564
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_055130"
SQ   SEQUENCE   564 AA;  61565 MW;  BB6700D6EAEC2B20 CRC64;
     MSSHGNSLFL RESGQRLGRV GWLQRLQESL QQRALRTRLR LQTMTLEHVL RFLRRNAFIL
     LTVSAVVIGV SLAFALRPYQ LTYRQIKYFS FPGELLMRML QMLVLPLIVS SLVTGMASLD
     NKATGRMGMR AAVYYMVTTI IAVFIGILMV TIIHPGKGSK EGLHREGRIE TIPTADAFMD
     LIRNMFPPNL VEACFKQFKT QYSTRVVTRT MVRTENGSEP GASMPPPFSV ENGTSFLENV
     TRALGTLQEM LSFEETVPVP GSANGINALG LVVFSVAFGL VIGGMKHKGR VLRDFFDSLN
     EAIMRLVGII IWYAPVGILF LIAGKILEME DMAVLGGQLG MYTLTVIVGL FLHAGIVLPL
     IYFLVTHRNP FPFIGGMLQA LITAMGTSSS SATLPITFRC LEEGLGVDRR ITRFVLPVGA
     TVNMDGTALY EALAAIFIAQ VNNYELNLGQ ITTISITATA ASVGAAGIPQ AGLVTMVIVL
     TSVGLPTEDI TLIIAVDWFL DRLRTMTNVL GDSIGAAVIE HLSQRELELQ EAELTLPSLG
     KPYKSLMAQE KGASRGRGGN ESAM
 
 
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