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Protein

Excitatory amino acid transporter 1

Gene

SLC1A3

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:8123008, PubMed:20477940, PubMed:26690923, PubMed:28032905, PubMed:28424515). Functions as a symporter that transports one amino acid molecule together with two or three Na+ ions and one proton, in parallel with the counter-transport of one K+ ion (PubMed:20477940). Mediates Cl- flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na+ symport (PubMed:20477940). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity).By similarity6 Publications

Kineticsi

  1. KM=525 µM for L-glutamate1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi394Sodium 1; via carbonyl oxygenBy similarity1
    Metal bindingi396Sodium 2; via carbonyl oxygenCombined sources1 Publication1
    Metal bindingi398Sodium 1By similarity1
    Binding sitei402AspartateCombined sources1 Publication1
    Binding sitei476AspartateCombined sources1 Publication1
    Metal bindingi483Sodium 1; via carbonyl oxygenBy similarity1
    Binding sitei483AspartateCombined sources1 Publication1
    Metal bindingi487Sodium 1By similarity1

    GO - Molecular functioni

    • amino acid transmembrane transporter activity Source: Reactome
    • glutamate:sodium symporter activity Source: UniProtKB
    • glutamate binding Source: Ensembl
    • high-affinity glutamate transmembrane transporter activity Source: UniProtKB
    • L-glutamate transmembrane transporter activity Source: BHF-UCL
    • metal ion binding Source: UniProtKB-KW

    GO - Biological processi

    • auditory behavior Source: Ensembl
    • cell morphogenesis involved in neuron differentiation Source: Ensembl
    • chemical synaptic transmission Source: ProtInc
    • chloride transmembrane transport Source: UniProtKB
    • cranial nerve development Source: Ensembl
    • D-aspartate import Source: UniProtKB
    • D-aspartate import across plasma membrane Source: UniProtKB
    • gamma-aminobutyric acid biosynthetic process Source: Ensembl
    • glutamate biosynthetic process Source: Ensembl
    • glutamate secretion Source: Reactome
    • ion transport Source: Reactome
    • L-aspartate import across plasma membrane Source: UniProtKB
    • L-glutamate import Source: UniProtKB
    • L-glutamate import across plasma membrane Source: UniProtKB
    • L-glutamate transmembrane transport Source: UniProtKB
    • neuromuscular process controlling balance Source: Ensembl
    • neurotransmitter uptake Source: ProtInc
    • positive regulation of synaptic transmission Source: Ensembl
    • potassium ion transmembrane transport Source: UniProtKB
    • response to antibiotic Source: Ensembl
    • response to drug Source: Ensembl
    • response to light stimulus Source: Ensembl
    • response to wounding Source: Ensembl
    • sensory perception of sound Source: Ensembl

    Keywordsi

    Biological processAmino-acid transport, Symport, Transport
    LigandChloride, Metal-binding, Potassium, Sodium

    Enzyme and pathway databases

    ReactomeiR-HSA-210455. Astrocytic Glutamate-Glutamine Uptake And Metabolism.
    R-HSA-210500. Glutamate Neurotransmitter Release Cycle.
    R-HSA-425393. Transport of inorganic cations/anions and amino acids/oligopeptides.

    Protein family/group databases

    TCDBi2.A.23.2.6. the dicarboxylate/amino acid:cation (na(+) or h(+)) symporter (daacs) family.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Excitatory amino acid transporter 12 Publications
    Alternative name(s):
    Sodium-dependent glutamate/aspartate transporter 11 Publication
    Short name:
    GLAST-11 Publication
    Solute carrier family 1 member 3
    Gene namesi
    Name:SLC1A3
    Synonyms:EAAT12 Publications, GLAST, GLAST11 Publication
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 5

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000079215.13.
    HGNCiHGNC:10941. SLC1A3.

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Topology

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Topological domaini1 – 47Cytoplasmic1 PublicationAdd BLAST47
    Transmembranei48 – 68Helical; Name=11 PublicationAdd BLAST21
    Topological domaini69 – 86Extracellular1 PublicationAdd BLAST18
    Transmembranei87 – 108Helical; Name=21 PublicationAdd BLAST22
    Topological domaini109 – 122Cytoplasmic1 PublicationAdd BLAST14
    Transmembranei123 – 145Helical; Name=31 PublicationAdd BLAST23
    Topological domaini146 – 236Extracellular1 PublicationAdd BLAST91
    Transmembranei237 – 260Helical; Name=41 PublicationAdd BLAST24
    Topological domaini261 – 269Cytoplasmic1 Publication9
    Transmembranei270 – 297Helical; Name=51 PublicationAdd BLAST28
    Topological domaini298 – 318Extracellular1 PublicationAdd BLAST21
    Transmembranei319 – 340Helical; Name=61 PublicationAdd BLAST22
    Topological domaini341 – 345Cytoplasmic1 Publication5
    Intramembranei346 – 376Discontinuously helical1 PublicationAdd BLAST31
    Topological domaini377 – 385Cytoplasmic1 Publication9
    Transmembranei386 – 412Helical; Name=71 PublicationAdd BLAST27
    Topological domaini413 – 425Extracellular1 PublicationAdd BLAST13
    Intramembranei426 – 459Discontinuously helical1 PublicationAdd BLAST34
    Topological domaini460 – 472Extracellular1 PublicationAdd BLAST13
    Transmembranei473 – 494Helical; Name=81 PublicationAdd BLAST22
    Topological domaini495 – 542Cytoplasmic1 PublicationAdd BLAST48

    Keywords - Cellular componenti

    Cell membrane, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Episodic ataxia 6 (EA6)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA disorder characterized by episodic ataxia, seizures, migraine and alternating hemiplegia.
    See also OMIM:612656
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_031733290P → R in EA6. 1 PublicationCorresponds to variant dbSNP:rs137852619Ensembl.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi363S → R: Loss of electrogenic glutamate transport. Strongly decreased L-aspartate and L-glutamate uptake combined with strongly increased permeability ot other ions; when associated with M-477. 1 Publication1
    Mutagenesisi477R → M: Strongly decreased L-aspartate and L-glutamate uptake combined with strongly increased permeability ot other ions; when associated with R-363. 1 Publication1
    Mutagenesisi523Y → F: No effect on activity. 1 Publication1

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    DisGeNETi6507.
    MalaCardsiSLC1A3.
    MIMi612656. phenotype.
    OpenTargetsiENSG00000079215.
    Orphaneti2131. Alternating hemiplegia of childhood.
    209967. Episodic ataxia type 6.
    PharmGKBiPA35828.

    Chemistry databases

    ChEMBLiCHEMBL3085.
    DrugBankiDB00142. L-Glutamic Acid.
    GuidetoPHARMACOLOGYi868.

    Polymorphism and mutation databases

    BioMutaiSLC1A3.
    DMDMi1169458.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002020571 – 542Excitatory amino acid transporter 1Add BLAST542

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei512PhosphoserineCombined sources1

    Post-translational modificationi

    Glycosylated.By similarity

    Keywords - PTMi

    Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiP43003.
    PaxDbiP43003.
    PeptideAtlasiP43003.
    PRIDEiP43003.

    PTM databases

    iPTMnetiP43003.
    PhosphoSitePlusiP43003.
    SwissPalmiP43003.

    Expressioni

    Tissue specificityi

    Detected in brain (PubMed:8218410, PubMed:7521911, PubMed:8123008). Detected at very much lower levels in heart, lung, placenta and skeletal muscle (PubMed:7521911, PubMed:8123008). Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia (PubMed:7521911).3 Publications

    Gene expression databases

    BgeeiENSG00000079215.
    CleanExiHS_SLC1A3.
    ExpressionAtlasiP43003. baseline and differential.
    GenevisibleiP43003. HS.

    Organism-specific databases

    HPAiCAB002573.
    HPA037467.
    HPA037468.

    Interactioni

    Subunit structurei

    Homotrimer.1 Publication

    Protein-protein interaction databases

    BioGridi112398. 7 interactors.
    IntActiP43003. 4 interactors.
    MINTiMINT-5004226.
    STRINGi9606.ENSP00000265113.

    Chemistry databases

    BindingDBiP43003.

    Structurei

    Secondary structure

    1542
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi41 – 47Combined sources7
    Helixi49 – 68Combined sources20
    Helixi75 – 81Combined sources7
    Helixi83 – 109Combined sources27
    Helixi113 – 142Combined sources30

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5LLMX-ray3.25A1-148[»]
    A243-542[»]
    5LLUX-ray3.32A1-148[»]
    A243-542[»]
    5LM4X-ray3.10A1-148[»]
    A243-542[»]
    5MJUX-ray3.71A1-148[»]
    A243-542[»]
    ProteinModelPortaliP43003.
    SMRiP43003.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni363 – 365Aspartate bindingCombined sources1 Publication3
    Regioni443 – 447Aspartate bindingCombined sources1 Publication5

    Domaini

    Contains eight transmembrane regions plus two helical hairpins that dip into the membrane. These helical hairpin structures play an important role in the transport process. The first enters the membrane from the cytoplasmic side, the second one from the extracellular side. During the transport cycle, the regions involved in amino acid transport, and especially the helical hairpins, move vertically by about 15-18 Angstroms, alternating between exposure to the aqueous phase and reinsertion in the lipid bilayer. In contrast, the regions involved in trimerization do not move.1 Publication

    Sequence similaritiesi

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG3787. Eukaryota.
    COG1301. LUCA.
    GeneTreeiENSGT00760000119117.
    HOGENOMiHOG000208776.
    HOVERGENiHBG000080.
    InParanoidiP43003.
    KOiK05614.
    OMAiTFAFSSR.
    OrthoDBiEOG091G0UCE.
    PhylomeDBiP43003.
    TreeFamiTF315206.

    Family and domain databases

    Gene3Di1.10.3860.10. 1 hit.
    InterProiView protein in InterPro
    IPR001991. Na-dicarboxylate_symporter.
    IPR018107. Na-dicarboxylate_symporter_CS.
    PfamiView protein in Pfam
    PF00375. SDF. 1 hit.
    PRINTSiPR00173. EDTRNSPORT.
    SUPFAMiSSF118215. SSF118215. 2 hits.
    PROSITEiView protein in PROSITE
    PS00713. NA_DICARBOXYL_SYMP_1. 1 hit.
    PS00714. NA_DICARBOXYL_SYMP_2. 1 hit.

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P43003-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MTKSNGEEPK MGGRMERFQQ GVRKRTLLAK KKVQNITKED VKSYLFRNAF
    60 70 80 90 100
    VLLTVTAVIV GTILGFTLRP YRMSYREVKY FSFPGELLMR MLQMLVLPLI
    110 120 130 140 150
    ISSLVTGMAA LDSKASGKMG MRAVVYYMTT TIIAVVIGII IVIIIHPGKG
    160 170 180 190 200
    TKENMHREGK IVRVTAADAF LDLIRNMFPP NLVEACFKQF KTNYEKRSFK
    210 220 230 240 250
    VPIQANETLV GAVINNVSEA METLTRITEE LVPVPGSVNG VNALGLVVFS
    260 270 280 290 300
    MCFGFVIGNM KEQGQALREF FDSLNEAIMR LVAVIMWYAP VGILFLIAGK
    310 320 330 340 350
    IVEMEDMGVI GGQLAMYTVT VIVGLLIHAV IVLPLLYFLV TRKNPWVFIG
    360 370 380 390 400
    GLLQALITAL GTSSSSATLP ITFKCLEENN GVDKRVTRFV LPVGATINMD
    410 420 430 440 450
    GTALYEALAA IFIAQVNNFE LNFGQIITIS ITATAASIGA AGIPQAGLVT
    460 470 480 490 500
    MVIVLTSVGL PTDDITLIIA VDWFLDRLRT TTNVLGDSLG AGIVEHLSRH
    510 520 530 540
    ELKNRDVEMG NSVIEENEMK KPYQLIAQDN ETEKPIDSET KM
    Length:542
    Mass (Da):59,572
    Last modified:November 1, 1995 - v1
    Checksum:i6E9F62D35A3A5A29
    GO
    Isoform 2 (identifier: P43003-2) [UniParc]FASTAAdd to basket
    Also known as: EAAT1ex9skip

    The sequence of this isoform differs from the canonical sequence as follows:
         430-475: SITATAASIGAAGIPQAGLVTMVIVLTSVGLPTDDITLIIAVDWFL → R

    Note: Expressed throughout the CNS, both in gray matter and axonal tracts, at levels ranging between 10% and 20% of isoform 1. Localizes to ER, has no functional glutamate uptake activity, and exerts a dominant negative effect isoform 1.
    Show »
    Length:497
    Mass (Da):55,149
    Checksum:i7C21EC2B467E1C11
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti366S → CT (PubMed:8218410).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_011877219E → D. Corresponds to variant dbSNP:rs2032892Ensembl.1
    Natural variantiVAR_031733290P → R in EA6. 1 PublicationCorresponds to variant dbSNP:rs137852619Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_043913430 – 475SITAT…VDWFL → R in isoform 2. 1 PublicationAdd BLAST46

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    L19158 mRNA. No translation available.
    U03504 mRNA. Translation: AAA50428.1.
    D26443 mRNA. Translation: BAA05462.1.
    Z31713
    , Z31703, Z31704, Z31705, Z31706, Z31707, Z31708, Z31709, Z31710 Genomic DNA. Translation: CAA83507.1.
    AY954110 mRNA. Translation: AAY28724.1.
    AK312304 mRNA. Translation: BAG35230.1.
    AC008957 Genomic DNA. No translation available.
    AC010631 Genomic DNA. No translation available.
    CH471119 Genomic DNA. Translation: EAW55945.1.
    CCDSiCCDS3919.1. [P43003-1]
    CCDS54844.1. [P43003-2]
    PIRiS38353.
    RefSeqiNP_001160167.1. NM_001166695.2. [P43003-2]
    NP_001276869.1. NM_001289940.1.
    NP_004163.3. NM_004172.4. [P43003-1]
    XP_005248399.1. XM_005248342.2. [P43003-1]
    UniGeneiHs.481918.

    Genome annotation databases

    EnsembliENST00000265113; ENSP00000265113; ENSG00000079215. [P43003-1]
    ENST00000381918; ENSP00000371343; ENSG00000079215. [P43003-2]
    GeneIDi6507.
    KEGGihsa:6507.
    UCSCiuc003jkj.4. human. [P43003-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiEAA1_HUMAN
    AccessioniPrimary (citable) accession number: P43003
    Secondary accession number(s): B2R5T3, Q4JCQ8
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
    Last sequence update: November 1, 1995
    Last modified: September 27, 2017
    This is version 164 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 5
      Human chromosome 5: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families