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Protein

Glutamate receptor ionotropic, NMDA 2D

Gene

GRIN2D

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

Functioni

Component of NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg2+ (PubMed:9489750, PubMed:27616483, PubMed:26875626, PubMed:28126851). Sensitivity to glutamate and channel kinetics depend on the subunit composition (PubMed:9489750).5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei541GlutamateBy similarity1
Binding sitei546GlutamateBy similarity1
Sitei642Functional determinant of NMDA receptorsBy similarity1
Binding sitei759GlutamateBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionIon channel, Ligand-gated ion channel, Receptor
Biological processIon transport, Transport
LigandCalcium, Magnesium

Enzyme and pathway databases

ReactomeiR-HSA-438066 Unblocking of NMDA receptor, glutamate binding and activation
R-HSA-442729 CREB phosphorylation through the activation of CaMKII
R-HSA-442982 Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-6794361 Neurexins and neuroligins
R-HSA-8849932 Synaptic adhesion-like molecules
SignaLinkiO15399

Names & Taxonomyi

Protein namesi
Recommended name:
Glutamate receptor ionotropic, NMDA 2D
Short name:
GluN2D
Alternative name(s):
EB11
Glutamate [NMDA] receptor subunit epsilon-4
N-methyl D-aspartate receptor subtype 2D
Short name:
NMDAR2D
Short name:
NR2D
Gene namesi
Name:GRIN2D
Synonyms:GluN2D, NMDAR2D
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000105464.3
HGNCiHGNC:4588 GRIN2D
MIMi602717 gene
neXtProtiNX_O15399

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 domaini28 – 584ExtracellularBy similarityAdd BLAST557
Transmembranei585 – 603HelicalBy similarityAdd BLAST19
Topological domaini604 – 630CytoplasmicBy similarityAdd BLAST27
Intramembranei631 – 650Discontinuously helicalBy similarityAdd BLAST20
Topological domaini651 – 657CytoplasmicBy similarity7
Transmembranei658 – 673HelicalBy similarityAdd BLAST16
Topological domaini674 – 844ExtracellularBy similarityAdd BLAST171
Transmembranei845 – 864HelicalBy similarityAdd BLAST20
Topological domaini865 – 1336CytoplasmicBy similarityAdd BLAST472

Keywords - Cellular componenti

Cell junction, Cell membrane, Membrane, Postsynaptic cell membrane, Synapse

Pathology & Biotechi

Involvement in diseasei

Epileptic encephalopathy, early infantile, 46 (EIEE46)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.
See also OMIM:617162
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_077103667V → I in EIEE46; gain-of-function mutation that potentiates ionotropic glutamate receptor signaling; mutant receptors are activated by lower concentrations of glutamate and glycine and show slower deactivation after agonist removal as well as decreased sensitivity to allosteric inhibitors indicating that NMDA glutamate receptor activity is changed. 1 PublicationCorresponds to variant dbSNP:rs886040861EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi580P → R: Changed glutamate-gated calcium ion channel activity characterized by increased glutamate and glycine potency. 1 Publication1
Mutagenesisi845M → V: Increased glutamate and glycine agonist potency. 1 Publication1

Keywords - Diseasei

Disease mutation, Epilepsy

Organism-specific databases

DisGeNETi2906
MalaCardsiGRIN2D
MIMi617162 phenotype
OpenTargetsiENSG00000105464
PharmGKBiPA28982

Chemistry databases

ChEMBLiCHEMBL2591
DrugBankiDB00659 Acamprosate
DB06151 Acetylcysteine
DB00289 Atomoxetine
DB00996 Gabapentin
DB06741 Gavestinel
DB06738 Ketobemidone
DB00142 L-Glutamic Acid
DB04896 Milnacipran
DB01173 Orphenadrine
DB00312 Pentobarbital
DB00454 Pethidine
DB01174 Phenobarbital
DB01708 Prasterone
DB00418 Secobarbital
DB01520 Tenocyclidine

Polymorphism and mutation databases

BioMutaiGRIN2D

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 27Sequence analysisAdd BLAST27
ChainiPRO_000001158328 – 1336Glutamate receptor ionotropic, NMDA 2DAdd BLAST1309

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi92N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi104 ↔ 348By similarity
Glycosylationi352N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi366N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi455 ↔ 483By similarity
Disulfide bondi462 ↔ 484By similarity
Glycosylationi467N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi569N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi773 ↔ 828By similarity
Modified residuei1316Omega-N-methylarginineBy similarity1
Modified residuei1326PhosphoserineBy similarity1

Keywords - PTMi

Disulfide bond, Glycoprotein, Methylation, Phosphoprotein

Proteomic databases

EPDiO15399
PaxDbiO15399
PeptideAtlasiO15399
PRIDEiO15399
ProteomicsDBi48638

PTM databases

iPTMnetiO15399
PhosphoSitePlusiO15399

Expressioni

Gene expression databases

BgeeiENSG00000105464 Expressed in 83 organ(s), highest expression level in hypothalamus
CleanExiHS_GRIN2D
GenevisibleiO15399 HS

Interactioni

Subunit structurei

Heterotetramer. Forms heterotetrameric channels composed of two zeta subunits (GRIN1), and two epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) (in vitro) (PubMed:9489750, PubMed:26875626, PubMed:28126851). In vivo, the subunit composition may depend on the expression levels of the different subunits (Probable). Interacts with PDZ domains of PATJ and DLG4 (By similarity).By similarityCurated3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Dlg3Q629362EBI-1754030,EBI-349596From Rattus norvegicus.

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109163, 3 interactors
ComplexPortaliCPX-289 NMDA receptor complex, GluN1-GluN2D
IntActiO15399, 4 interactors
MINTiO15399
STRINGi9606.ENSP00000263269

Chemistry databases

BindingDBiO15399

Structurei

3D structure databases

ProteinModelPortaliO15399
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni539 – 541Glutamate bindingBy similarity3
Regioni631 – 650Pore-formingBy similarityAdd BLAST20
Regioni717 – 718Glutamate bindingBy similarity2

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1334 – 1336PDZ-bindingBy similarity3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi281 – 286Poly-Gly6
Compositional biasi908 – 916Poly-Pro9
Compositional biasi1035 – 1040Poly-Ala6
Compositional biasi1209 – 1213Poly-Pro5
Compositional biasi1244 – 1247Poly-Ala4

Domaini

A hydrophobic region that gives rise to the prediction of a transmembrane span does not cross the membrane, but is part of a discontinuously helical region that dips into the membrane and is probably part of the pore and of the selectivity filter.By similarity

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1053 Eukaryota
ENOG410XNUR LUCA
GeneTreeiENSGT00910000143978
HOGENOMiHOG000113803
HOVERGENiHBG052637
InParanoidiO15399
KOiK05212
OMAiWDYLPPR
OrthoDBiEOG091G09KH
PhylomeDBiO15399
TreeFamiTF314731

Family and domain databases

InterProiView protein in InterPro
IPR001828 ANF_lig-bd_rcpt
IPR019594 Glu/Gly-bd
IPR001508 Iono_rcpt_met
IPR001320 Iontro_rcpt
IPR028082 Peripla_BP_I
PfamiView protein in Pfam
PF01094 ANF_receptor, 1 hit
PF00060 Lig_chan, 1 hit
PF10613 Lig_chan-Glu_bd, 1 hit
PRINTSiPR00177 NMDARECEPTOR
SMARTiView protein in SMART
SM00918 Lig_chan-Glu_bd, 1 hit
SM00079 PBPe, 1 hit
SUPFAMiSSF53822 SSF53822, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O15399-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MRGAGGPRGP RGPAKMLLLL ALACASPFPE EAPGPGGAGG PGGGLGGARP
60 70 80 90 100
LNVALVFSGP AYAAEAARLG PAVAAAVRSP GLDVRPVALV LNGSDPRSLV
110 120 130 140 150
LQLCDLLSGL RVHGVVFEDD SRAPAVAPIL DFLSAQTSLP IVAVHGGAAL
160 170 180 190 200
VLTPKEKGST FLQLGSSTEQ QLQVIFEVLE EYDWTSFVAV TTRAPGHRAF
210 220 230 240 250
LSYIEVLTDG SLVGWEHRGA LTLDPGAGEA VLSAQLRSVS AQIRLLFCAR
260 270 280 290 300
EEAEPVFRAA EEAGLTGSGY VWFMVGPQLA GGGGSGAPGE PPLLPGGAPL
310 320 330 340 350
PAGLFAVRSA GWRDDLARRV AAGVAVVARG AQALLRDYGF LPELGHDCRA
360 370 380 390 400
QNRTHRGESL HRYFMNITWD NRDYSFNEDG FLVNPSLVVI SLTRDRTWEV
410 420 430 440 450
VGSWEQQTLR LKYPLWSRYG RFLQPVDDTQ HLTVATLEER PFVIVEPADP
460 470 480 490 500
ISGTCIRDSV PCRSQLNRTH SPPPDAPRPE KRCCKGFCID ILKRLAHTIG
510 520 530 540 550
FSYDLYLVTN GKHGKKIDGV WNGMIGEVFY QRADMAIGSL TINEERSEIV
560 570 580 590 600
DFSVPFVETG ISVMVARSNG TVSPSAFLEP YSPAVWVMMF VMCLTVVAVT
610 620 630 640 650
VFIFEYLSPV GYNRSLATGK RPGGSTFTIG KSIWLLWALV FNNSVPVENP
660 670 680 690 700
RGTTSKIMVL VWAFFAVIFL ASYTANLAAF MIQEEYVDTV SGLSDRKFQR
710 720 730 740 750
PQEQYPPLKF GTVPNGSTEK NIRSNYPDMH SYMVRYNQPR VEEALTQLKA
760 770 780 790 800
GKLDAFIYDA AVLNYMARKD EGCKLVTIGS GKVFATTGYG IALHKGSRWK
810 820 830 840 850
RPIDLALLQF LGDDEIEMLE RLWLSGICHN DKIEVMSSKL DIDNMAGVFY
860 870 880 890 900
MLLVAMGLSL LVFAWEHLVY WRLRHCLGPT HRMDFLLAFS RGMYSCCSAE
910 920 930 940 950
AAPPPAKPPP PPQPLPSPAY PAPRPAPGPA PFVPRERASV DRWRRTKGAG
960 970 980 990 1000
PPGGAGLADG FHRYYGPIEP QGLGLGLGEA RAAPRGAAGR PLSPPAAQPP
1010 1020 1030 1040 1050
QKPPPSYFAI VRDKEPAEPP AGAFPGFPSP PAPPAAAATA VGPPLCRLAF
1060 1070 1080 1090 1100
EDESPPAPAR WPRSDPESQP LLGPGAGGAG GTGGAGGGAP AAPPPCRAAP
1110 1120 1130 1140 1150
PPCPYLDLEP SPSDSEDSES LGGASLGGLE PWWFADFPYP YAERLGPPPG
1160 1170 1180 1190 1200
RYWSVDKLGG WRAGSWDYLP PRSGPAAWHC RHCASLELLP PPRHLSCSHD
1210 1220 1230 1240 1250
GLDGGWWAPP PPPWAAGPLP RRRARCGCPR SHPHRPRASH RTPAAAAPHH
1260 1270 1280 1290 1300
HRHRRAAGGW DLPPPAPTSR SLEDLSSCPR AAPARRLTGP SRHARRCPHA
1310 1320 1330
AHWGPPLPTA SHRRHRGGDL GTRRGSAHFS SLESEV
Length:1,336
Mass (Da):143,752
Last modified:May 5, 2009 - v2
Checksum:i0DB7559056AE4593
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti924R → G in AAC15910 (PubMed:9489750).Curated1
Sequence conflicti1005P → A in AAC15910 (PubMed:9489750).Curated1
Sequence conflicti1097R → C in AAC15910 (PubMed:9489750).Curated1
Sequence conflicti1130E → D in AAC15910 (PubMed:9489750).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_035698140P → S in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_035699286G → R in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_079975466L → V Found in a patient with schizophrenia; unknown pathological significance. 1 Publication1
Natural variantiVAR_035700527E → G in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_079976592M → L Found in a patient with autism spectrum disorder; unknown pathological significance. 1 Publication1
Natural variantiVAR_077103667V → I in EIEE46; gain-of-function mutation that potentiates ionotropic glutamate receptor signaling; mutant receptors are activated by lower concentrations of glutamate and glycine and show slower deactivation after agonist removal as well as decreased sensitivity to allosteric inhibitors indicating that NMDA glutamate receptor activity is changed. 1 PublicationCorresponds to variant dbSNP:rs886040861EnsemblClinVar.1
Natural variantiVAR_079977733M → V Found in a patient with schizophrenia; unknown pathological significance. 1 Publication1
Natural variantiVAR_079978872R → H Found in a patient with schizophrenia; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs750543659Ensembl.1
Natural variantiVAR_079979883M → I1 PublicationCorresponds to variant dbSNP:rs781567305Ensembl.1
Natural variantiVAR_079980922A → V Found in patients with schizophrenia; unknown pathological significance. 1 PublicationCorresponds to variant dbSNP:rs571334598EnsemblClinVar.1
Natural variantiVAR_079981926A → T Found in a patient with autism spectrum disorder; unknown pathological significance. 1 Publication1
Natural variantiVAR_079982982A → P1 Publication1
Natural variantiVAR_0799831317G → S1 PublicationCorresponds to variant dbSNP:rs191119443Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U77783 mRNA Translation: AAC15910.1
AC008403 Genomic DNA No translation available.
AC011527 Genomic DNA No translation available.
CCDSiCCDS12719.1
RefSeqiNP_000827.2, NM_000836.2
XP_011525174.1, XM_011526872.1
UniGeneiHs.445015

Genome annotation databases

EnsembliENST00000263269; ENSP00000263269; ENSG00000105464
GeneIDi2906
KEGGihsa:2906
UCSCiuc002pjc.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNMDE4_HUMAN
AccessioniPrimary (citable) accession number: O15399
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 29, 2001
Last sequence update: May 5, 2009
Last modified: September 12, 2018
This is version 166 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
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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