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Protein

Excitatory amino acid transporter 3

Gene

SLC1A1

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:7914198, PubMed:7521911, PubMed:8857541, PubMed:26690923, PubMed:21123949). Can also transport L-cysteine (PubMed:21123949). 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:7521911, PubMed:8857541, PubMed:26690923). 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:8857541, PubMed:26690923). Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli (PubMed:21123949). 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). Negatively regulated by ARL6IP5 (By similarity).By similarity5 Publications

Kineticsi

  1. KM=268 µM for L-glutamate1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi362Sodium 1; via carbonyl oxygenBy similarity1
    Metal bindingi364Sodium 2; via carbonyl oxygenBy similarity1
    Metal bindingi366Sodium 1By similarity1
    Binding sitei370AspartateBy similarity1
    Binding sitei444AspartateBy similarity1
    Metal bindingi451Sodium 1; via carbonyl oxygenBy similarity1
    Binding sitei451AspartateBy similarity1
    Metal bindingi455Sodium 1By similarity1

    GO - Molecular functioni

    • amino acid transmembrane transporter activity Source: Reactome
    • chloride transmembrane transporter activity Source: UniProtKB
    • cysteine transmembrane transporter activity Source: UniProtKB
    • glutamate:sodium symporter activity Source: UniProtKB
    • glutamate binding Source: Ensembl
    • high-affinity glutamate transmembrane transporter activity Source: UniProtKB
    • L-glutamate transmembrane transporter activity Source: UniProtKB

    GO - Biological processi

    • chemical synaptic transmission Source: ProtInc
    • chloride transmembrane transport Source: UniProtKB
    • cysteine transport Source: UniProtKB
    • D-aspartate import Source: UniProtKB
    • D-aspartate import across plasma membrane Source: UniProtKB
    • 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
    • positive regulation of heart rate Source: Ensembl
    • protein homooligomerization Source: Ensembl

    Keywordsi

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

    Enzyme and pathway databases

    ReactomeiR-HSA-210500. Glutamate Neurotransmitter Release Cycle.
    R-HSA-425393. Transport of inorganic cations/anions and amino acids/oligopeptides.

    Protein family/group databases

    TCDBi2.A.23.2.3. the dicarboxylate/amino acid:cation (na(+) or h(+)) symporter (daacs) family.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Excitatory amino acid transporter 3
    Alternative name(s):
    Excitatory amino-acid carrier 1
    Neuronal and epithelial glutamate transporter
    Sodium-dependent glutamate/aspartate transporter 3
    Solute carrier family 1 member 1
    Gene namesi
    Name:SLC1A1
    Synonyms:EAAC1, EAAT3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 9

    Organism-specific databases

    HGNCiHGNC:10939. SLC1A1.

    Subcellular locationi

    Topology

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Topological domaini1 – 18CytoplasmicCuratedAdd BLAST18
    Transmembranei19 – 38HelicalSequence analysisAdd BLAST20
    Topological domaini39 – 61ExtracellularCuratedAdd BLAST23
    Transmembranei62 – 82HelicalSequence analysisAdd BLAST21
    Topological domaini83 – 93CytoplasmicCuratedAdd BLAST11
    Transmembranei94 – 114HelicalSequence analysisAdd BLAST21
    Topological domaini115 – 205ExtracellularCuratedAdd BLAST91
    Transmembranei206 – 229Helical; Name=4By similarityAdd BLAST24
    Topological domaini230 – 238CytoplasmicCurated9
    Transmembranei239 – 266Helical; Name=5By similarityAdd BLAST28
    Topological domaini267 – 286ExtracellularCuratedAdd BLAST20
    Transmembranei287 – 308Helical; Name=6By similarityAdd BLAST22
    Topological domaini309 – 313CytoplasmicCurated5
    Intramembranei314 – 344Discontinuously helicalBy similarityAdd BLAST31
    Topological domaini345 – 353CytoplasmicCurated9
    Transmembranei354 – 380Helical; Name=7By similarityAdd BLAST27
    Topological domaini381 – 393ExtracellularCuratedAdd BLAST13
    Intramembranei394 – 427Discontinuously helicalBy similarityAdd BLAST34
    Topological domaini428 – 440ExtracellularCuratedAdd BLAST13
    Transmembranei441 – 462Helical; Name=8By similarityAdd BLAST22
    Topological domaini463 – 524CytoplasmicCuratedAdd BLAST62

    GO - Cellular componenti

    • apical plasma membrane Source: UniProtKB
    • extracellular exosome Source: UniProtKB
    • integral component of plasma membrane Source: UniProtKB
    • membrane Source: ProtInc
    • plasma membrane Source: UniProtKB

    Keywords - Cellular componenti

    Cell membrane, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Dicarboxylic aminoaciduria (DCBXA)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionAn autosomal recessive disorder characterized by abnormal excretion of urinary glutamate and aspartate, resulting from the incomplete reabsorption of anionic amino acids from the glomerular filtrate in the kidney. It can be associated with mental retardation.
    See also OMIM:222730
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_071953395Missing in DCBXA; inhibits L-glutamate and L-cysteine transport activities. 1 Publication1
    Natural variantiVAR_071954445R → W in DCBXA; reduces L-glutamate and L-cysteine transport activities; reduces cell membrane expression. 1 PublicationCorresponds to variant dbSNP:rs587777696Ensembl.1
    Schizophrenia 18 (SCZD18)2 Publications
    Disease susceptibility is associated with variations affecting the gene represented in this entry. A deletion at the chromosome 9p24.2 locus, including SLC1A1, has been identified in patients with psychotic disorders (PubMed:21982423). This 84 kb deletion is immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, co-segregates with disease in an extended 5-generation pedigree and increases disease risk more than 18-fold for family members (PubMed:23341099).2 Publications
    Disease descriptionA complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder.
    See also OMIM:615232

    Keywords - Diseasei

    Disease mutation, Schizophrenia

    Organism-specific databases

    DisGeNETi6505.
    MalaCardsiSLC1A1.
    MIMi222730. phenotype.
    615232. phenotype.
    OpenTargetsiENSG00000106688.
    Orphaneti2195. Dicarboxylic aminoaciduria.
    3140. Schizophrenia.
    PharmGKBiPA35826.

    Chemistry databases

    ChEMBLiCHEMBL2721.
    DrugBankiDB00128. L-Aspartic Acid.
    DB00142. L-Glutamic Acid.
    DB00230. Pregabalin.
    GuidetoPHARMACOLOGYi870.

    Polymorphism and mutation databases

    BioMutaiSLC1A1.
    DMDMi1352332.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002020651 – 524Excitatory amino acid transporter 3Add BLAST524

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Glycosylationi43N-linked (GlcNAc...) asparagineSequence analysis1
    Glycosylationi178N-linked (GlcNAc...) asparagineSequence analysis1
    Glycosylationi195N-linked (GlcNAc...) asparagineSequence analysis1
    Modified residuei517PhosphoserineBy similarity1
    Modified residuei522PhosphoserineBy similarity1

    Post-translational modificationi

    Glycosylated.

    Keywords - PTMi

    Glycoprotein, Phosphoprotein

    Proteomic databases

    EPDiP43005.
    MaxQBiP43005.
    PaxDbiP43005.
    PeptideAtlasiP43005.
    PRIDEiP43005.

    PTM databases

    iPTMnetiP43005.
    PhosphoSitePlusiP43005.

    Expressioni

    Tissue specificityi

    Expressed in all tissues tested including liver, muscle, testis, ovary, retinoblastoma cell line, neurons and brain (in which there was dense expression in substantia nigra, red nucleus, hippocampus and in cerebral cortical layers).3 Publications

    Gene expression databases

    BgeeiENSG00000106688.
    CleanExiHS_SLC1A1.
    ExpressionAtlasiP43005. baseline and differential.
    GenevisibleiP43005. HS.

    Organism-specific databases

    HPAiCAB015466.
    HPA020086.

    Interactioni

    Subunit structurei

    Homotrimer (Probable). Interacts with ARL6IP5 (By similarity).By similarityCurated

    Binary interactionsi

    Show more details

    Protein-protein interaction databases

    BioGridi112396. 33 interactors.
    IntActiP43005. 3 interactors.
    STRINGi9606.ENSP00000262352.

    Chemistry databases

    BindingDBiP43005.

    Structurei

    3D structure databases

    ProteinModelPortaliP43005.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni331 – 333Aspartate bindingBy similarity3
    Regioni411 – 415Aspartate bindingBy similarity5

    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.By similarity

    Sequence similaritiesi

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG3787. Eukaryota.
    COG1301. LUCA.
    GeneTreeiENSGT00760000119117.
    HOGENOMiHOG000208776.
    HOVERGENiHBG000080.
    InParanoidiP43005.
    KOiK05612.
    OMAiYLYIAVI.
    OrthoDBiEOG091G0UCE.
    PhylomeDBiP43005.
    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.

    Sequencei

    Sequence statusi: Complete.

    P43005-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MGKPARKGCE WKRFLKNNWV LLSTVAAVVL GITTGVLVRE HSNLSTLEKF
    60 70 80 90 100
    YFAFPGEILM RMLKLIILPL IISSMITGVA ALDSNVSGKI GLRAVVYYFC
    110 120 130 140 150
    TTLIAVILGI VLVVSIKPGV TQKVGEIART GSTPEVSTVD AMLDLIRNMF
    160 170 180 190 200
    PENLVQACFQ QYKTKREEVK PPSDPEMNMT EESFTAVMTT AISKNKTKEY
    210 220 230 240 250
    KIVGMYSDGI NVLGLIVFCL VFGLVIGKMG EKGQILVDFF NALSDATMKI
    260 270 280 290 300
    VQIIMCYMPL GILFLIAGKI IEVEDWEIFR KLGLYMATVL TGLAIHSIVI
    310 320 330 340 350
    LPLIYFIVVR KNPFRFAMGM AQALLTALMI SSSSATLPVT FRCAEENNQV
    360 370 380 390 400
    DKRITRFVLP VGATINMDGT ALYEAVAAVF IAQLNDLDLG IGQIITISIT
    410 420 430 440 450
    ATSASIGAAG VPQAGLVTMV IVLSAVGLPA EDVTLIIAVD WLLDRFRTMV
    460 470 480 490 500
    NVLGDAFGTG IVEKLSKKEL EQMDVSSEVN IVNPFALEST ILDNEDSDTK
    510 520
    KSYVNGGFAV DKSDTISFTQ TSQF
    Length:524
    Mass (Da):57,100
    Last modified:February 1, 1996 - v2
    Checksum:iFC6244ADC9EA228F
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti10E → PS in AAA50430 (PubMed:7521911).Curated1
    Sequence conflicti92L → V in AAH33040 (PubMed:15489334).Curated1
    Sequence conflicti94A → V in AAA68628 (PubMed:7859077).Curated1
    Sequence conflicti94A → V in AAC27511 (PubMed:11317217).Curated1
    Sequence conflicti96V → L in AAA53215 (PubMed:7914198).Curated1
    Sequence conflicti170K → N in AAA53215 (PubMed:7914198).Curated1
    Sequence conflicti172P → A in AAA53215 (PubMed:7914198).Curated1
    Sequence conflicti260L → H in AAA53215 (PubMed:7914198).Curated1
    Sequence conflicti280R → A in AAA68628 (PubMed:7859077).Curated1
    Sequence conflicti376V → G in AAC25029 (Ref. 8) Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_02330927A → G. Corresponds to variant dbSNP:rs2229885Ensembl.1
    Natural variantiVAR_02330850F → Y. Corresponds to variant dbSNP:rs2228621Ensembl.1
    Natural variantiVAR_071953395Missing in DCBXA; inhibits L-glutamate and L-cysteine transport activities. 1 Publication1
    Natural variantiVAR_071954445R → W in DCBXA; reduces L-glutamate and L-cysteine transport activities; reduces cell membrane expression. 1 PublicationCorresponds to variant dbSNP:rs587777696Ensembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U08989 mRNA. Translation: AAA68628.1.
    U06469 mRNA. Translation: AAA53215.1.
    U03506 mRNA. Translation: AAA50430.1.
    AF074911
    , AF143773, AF074903, AF074904, AF074905, AF074906, AF074907, AF074908, AF074909, AF074910 Genomic DNA. Translation: AAC27511.3.
    AB008536 mRNA. Translation: BAB83767.1.
    AL162587, AL136231 Genomic DNA. Translation: CAH71965.1.
    AL136231, AL162587 Genomic DNA. Translation: CAI41264.1.
    BC033040 mRNA. Translation: AAH33040.1.
    AF037982 mRNA. Translation: AAC25029.1.
    CCDSiCCDS6452.1.
    PIRiA54856.
    I38433.
    I38560.
    RefSeqiNP_004161.4. NM_004170.5.
    UniGeneiHs.444915.

    Genome annotation databases

    EnsembliENST00000262352; ENSP00000262352; ENSG00000106688.
    GeneIDi6505.
    KEGGihsa:6505.
    UCSCiuc003zij.3. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

    Entry informationi

    Entry nameiEAA3_HUMAN
    AccessioniPrimary (citable) accession number: P43005
    Secondary accession number(s): O75587
    , Q5VZ24, Q8N199, Q9UEW2
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1995
    Last sequence update: February 1, 1996
    Last modified: July 5, 2017
    This is version 156 of the entry and version 2 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

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 9
      Human chromosome 9: 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. SIMILARITY comments
      Index of protein domains and families