EAA4_RAT
ID EAA4_RAT Reviewed; 561 AA.
AC O35921; P97683;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=Excitatory amino acid transporter 4;
DE AltName: Full=High-affinity neuronal glutamate transporter;
DE AltName: Full=Sodium-dependent glutamate/aspartate transporter;
DE AltName: Full=Solute carrier family 1 member 6;
GN Name=Slc1a6; Synonyms=Eaat4;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Cerebellum;
RA Lin C.-L.G., Jin L., Rothstein J.D.;
RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 74-305.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RA Matthews J.C., Kilberg M.S., Novak D.A.;
RL Submitted (JAN-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=14506254; DOI=10.1074/jbc.m307990200;
RA Melzer N., Biela A., Fahlke C.;
RT "Glutamate modifies ion conduction and voltage-dependent gating of
RT excitatory amino acid transporter-associated anion channels.";
RL J. Biol. Chem. 278:50112-50119(2003).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
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:14506254, 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 (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino
CC acid transport; this avoids the accumulation of negative charges due to
CC aspartate and Na(+) symport (PubMed:14506254). Plays a redundant role
CC in the rapid removal of released glutamate from the synaptic cleft,
CC which is essential for terminating the postsynaptic action of glutamate
CC (Probable). {ECO:0000269|PubMed:14506254, ECO:0000269|PubMed:26690923,
CC ECO:0000305}.
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:0000250|UniProtKB:P48664};
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:0000250|UniProtKB:P48664};
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:0000250|UniProtKB:P48664};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=328 uM for L-glutamate {ECO:0000269|PubMed:26690923};
CC -!- SUBUNIT: Homotrimer. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26690923};
CC Multi-pass membrane protein {ECO:0000305}.
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; U89608; AAB72086.1; -; mRNA.
DR EMBL; U80915; AAB40997.1; -; mRNA.
DR RefSeq; NP_114454.1; NM_032065.1.
DR AlphaFoldDB; O35921; -.
DR SMR; O35921; -.
DR BioGRID; 249878; 2.
DR IntAct; O35921; 1.
DR MINT; O35921; -.
DR STRING; 10116.ENSRNOP00000009931; -.
DR BindingDB; O35921; -.
DR ChEMBL; CHEMBL3700; -.
DR GuidetoPHARMACOLOGY; 871; -.
DR GlyGen; O35921; 3 sites.
DR iPTMnet; O35921; -.
DR PhosphoSitePlus; O35921; -.
DR PaxDb; O35921; -.
DR PRIDE; O35921; -.
DR GeneID; 84012; -.
DR KEGG; rno:84012; -.
DR UCSC; RGD:620340; rat.
DR CTD; 6511; -.
DR RGD; 620340; Slc1a6.
DR eggNOG; KOG3787; Eukaryota.
DR InParanoid; O35921; -.
DR PhylomeDB; O35921; -.
DR Reactome; R-RNO-210500; Glutamate Neurotransmitter Release Cycle.
DR Reactome; R-RNO-425393; Transport of inorganic cations/anions and amino acids/oligopeptides.
DR PRO; PR:O35921; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0099055; C:integral component of postsynaptic membrane; IDA:SynGO.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:RGD.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0098796; C:membrane protein complex; IDA:ARUK-UCL.
DR GO; GO:0098688; C:parallel fiber to Purkinje cell synapse; IDA:SynGO.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0008509; F:anion transmembrane transporter activity; IDA:RGD.
DR GO; GO:0015501; F:glutamate:sodium symporter activity; IBA:GO_Central.
DR GO; GO:0005314; F:high-affinity L-glutamate transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015183; F:L-aspartate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0005313; F:L-glutamate transmembrane transporter activity; ISO:RGD.
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:0140009; P:L-aspartate import across plasma membrane; ISS:UniProtKB.
DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0015813; P:L-glutamate transmembrane transport; IDA:UniProtKB.
DR GO; GO:0001504; P:neurotransmitter uptake; ISO:RGD.
DR GO; GO:0042391; P:regulation of membrane potential; ISO:RGD.
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 Amino-acid transport; Cell membrane; Chloride; Glycoprotein; Membrane;
KW Metal-binding; Phosphoprotein; Potassium; Reference proteome; Sodium;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..561
FT /note="Excitatory amino acid transporter 4"
FT /id="PRO_0000202072"
FT TOPO_DOM 1..52
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 53..73
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 96..116
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 130..150
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 259..282
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT TRANSMEM 292..319
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT TRANSMEM 341..362
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT INTRAMEM 368..398
FT /note="Discontinuously helical"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT TRANSMEM 408..434
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT INTRAMEM 448..481
FT /note="Discontinuously helical"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT TRANSMEM 495..516
FT /note="Helical; Name=8"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 385..387
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 416
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O59010"
FT BINDING 418
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 420
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O59010"
FT BINDING 424
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 465..469
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 498
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 505
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250|UniProtKB:P43003"
FT BINDING 505
FT /ligand="Na(+)"
FT /ligand_id="ChEBI:CHEBI:29101"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O59010"
FT BINDING 509
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:0007744|PubMed:22673903"
FT CARBOHYD 213
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 229
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 236
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CONFLICT 119
FT /note="K -> R (in Ref. 2; AAB40997)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 561 AA; 60715 MW; AAF1298EE6AA8359 CRC64;
MSSHGNSLFL RESGAGGGCL QGLQDSLQQR ALRTRLRLQT MTREHVRRFL RRNAFILLTV
SAVIIGVSLA FALRPYQLTY RQIKYFSFPG ELLMRMLQML VLPLIVSSRV TGMASLDNKA
TGRMGMRAAV YYMVTTVIAV FIGILMVTII HPGKGSKEGL HREGRIETVP TADAFMDLVR
NMFPPNLVEA CFKQFKTQYS TRVVTRTIVR TDNGSELGAS ISPPSSAENE TSILENVTRA
LGTLQEVISF EETVPVPGSA NGINALGLVV FSVAFGLVIG GMKHKGRVLR DFFDSLNEAI
MRLVGIIIWY APVGILFLIA GKILEMEDMA VLGGQLGMYT LTVIVGLFLH AGGVLPLIYF
LVTHRNPFPF IGGILQALIT AMGTSSSSAT LPITFRCLEE GLGVDRRITR FVLPVGATVN
MDGTALYEAL AAIFIAQVNN YELNLGQITT ISITATAASV GAAGIPQAGL VTMVIVLTSV
GLPTEDITLI IAVDWFLDRL RTMTNVLGDS IGAAVIEHLS QRELELQEAE LTLPSLGKPY
KSLMAQAKGA SRGRGGNESV M
