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Protein

Eukaryotic translation initiation factor 4E-binding protein 2

Gene

EIF4EBP2

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

Functioni

Repressor of translation initiation involved in synaptic plasticity, learning and memory formation (By similarity). Regulates EIF4E activity by preventing its assembly into the eIF4F complex: hypophosphorylated form of EIF4EBP2 competes with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress translation. In contrast, hyperphosphorylated form dissociates from EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation (PubMed:25533957). EIF4EBP2 is enriched in brain and acts as a regulator of synapse activity and neuronal stem cell renewal via its ability to repress translation initiation (By similarity). Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways (By similarity).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Protein synthesis inhibitor

Keywords - Biological processi

Translation regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Eukaryotic translation initiation factor 4E-binding protein 21 Publication
Short name:
4E-BP21 Publication
Short name:
eIF4E-binding protein 21 Publication
Gene namesi
Name:EIF4EBP2Imported
OrganismiHomo sapiens (Human)Imported
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:3289. EIF4EBP2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi37 – 371T → D or E: Acidic residues do not mimic phosphorylation state. Does not induce folding of the intrinsically disordered protein; when associated with D-46 or E-46. 1 Publication
Mutagenesisi39 – 391G → V: Abolishes folding of the intrinsically disordered protein without affecting greatly affinity for EIF4E even when the protein is fully phosphorylated; when associated with V-48. 1 Publication
Mutagenesisi46 – 461T → D or E: Acidic residues do not mimic phosphorylation state. Does not induce folding of the intrinsically disordered protein; when associated with D-37 or E-37. 1 Publication
Mutagenesisi48 – 481G → V: Abolishes folding of the intrinsically disordered protein without affecting greatly affinity for EIF4E even when the protein is fully phosphorylated; when associated with V-39. 1 Publication
Mutagenesisi54 – 607YDRKFLL → AAAAAAA: Impaired binding to EIF4E. 1 Publication
Mutagenesisi78 – 825IPGVT → AAAAA: Impaired binding to EIF4E. 1 Publication

Organism-specific databases

PharmGKBiPA27716.

Polymorphism and mutation databases

BioMutaiEIF4EBP2.
DMDMi34921510.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 120120Eukaryotic translation initiation factor 4E-binding protein 2PRO_0000190516Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei37 – 371Phosphothreonine; by MTORCombined sources1 Publication
Modified residuei46 – 461Phosphothreonine; by MTORCombined sources1 Publication
Modified residuei65 – 651Phosphoserine; by MTOR1 Publication
Modified residuei70 – 701Phosphothreonine; by MTOR1 Publication
Modified residuei83 – 831Phosphoserine1 Publication
Modified residuei99 – 991Deamidated asparagineBy similarity
Modified residuei102 – 1021Deamidated asparagineBy similarity

Post-translational modificationi

Phosphorylation at Thr-37, Thr-46, Ser-65, Thr-70 and Ser-83 is mediated by MTOR and corresponds to the hyperphosphorylated form: it abolishes binding to EIF4E by inducing folding of intrinsically disordered regions (PubMed:24207126, PubMed:25533957). First phosphorylated at Thr-37 and Thr-46 by MTOR, inducing folding of region encompassing residues from Pro-18 to Arg-62 of into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a partly buried beta-strand, blocking accessibility to EIF4E. Protein phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize the fold, decreasing affinity for EIF4E by a factor of 4000 (PubMed:24207126, PubMed:25533957). Phosphorylated in response to insulin, EGF and PDGF.3 Publications
Deamidated at Asn-99 and Asn-102 to aspartate (Asp) in brain. Deamidation promotes interaction with RPTOR, subsequent phosphorylation by mTORC1 and increased translation, leading to impair kinetics of excitatory synaptic transmission. Deamidation takes place during postnatal development, when the PI3K-Akt-mTOR signaling is reduced, suggesting it acts as a compensatory mechanism to promote translation despite attenuated PI3K-Akt-mTOR signaling in neuron development. Deamidation converts Asn residues into a mixture of Asp and isoaspartate; interactions with PCMT1 is required to prevent isoaspartate accumulation and convert isoaspartate to Asp.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ13542.
MaxQBiQ13542.
PaxDbiQ13542.
PeptideAtlasiQ13542.
PRIDEiQ13542.

PTM databases

iPTMnetiQ13542.
PhosphoSiteiQ13542.

Expressioni

Gene expression databases

BgeeiQ13542.
CleanExiHS_EIF4EBP2.
ExpressionAtlasiQ13542. baseline and differential.
GenevisibleiQ13542. HS.

Organism-specific databases

HPAiCAB019415.
HPA037410.
HPA061665.

Interactioni

Subunit structurei

Hypophosphorylated EIF4EBP2 interacts with EIF4E; phosphorylation of EIF4EBP2 by mTORC1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation (PubMed:7935836, PubMed:24207126, PubMed:21661078, PubMed:25533957). Interacts with RPTOR; promoting phosphorylation by mTORC1 (By similarity). Interacts with PCMT1; required to prevent isoaspartate accumulation and convert isoaspartate to Asp (By similarity).By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
EIF4EP067304EBI-935137,EBI-73440

GO - Molecular functioni

Protein-protein interaction databases

BioGridi108294. 12 interactions.
DIPiDIP-36572N.
IntActiQ13542. 3 interactions.
MINTiMINT-1510996.
STRINGi9606.ENSP00000362314.

Structurei

Secondary structure

1
120
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi19 – 246Combined sources
Turni27 – 293Combined sources
Beta strandi42 – 454Combined sources
Helixi56 – 605Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2MX4NMR-A18-62[»]
3AM7X-ray2.20B47-65[»]
ProteinModelPortaliQ13542.
SMRiQ13542. Positions 18-62.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi54 – 607YXXXXLphi motif2 Publications
Motifi78 – 825Secondary EIF4E binding site2 Publications
Motifi116 – 1205TOS motifBy similarity

Domaini

The TOS motif mediates interaction with RPTOR, leading to promote phosphorylation by mTORC1 complex.By similarity
Intrinsically disordered protein that undergoes folding upon phosphorylation (PubMed:25533957). Hypophosphorylated form interacts strongly with EIF4E using (1) the YXXXXLPhi motif, that undergoes a disorder-to-helix transition upon binding and (2) the secondary EIF4E binding sites (residues 78-82) (PubMed:24207126, PubMed:25533957). Phosphorylation at Thr-37 and Thr-46 induces folding of region encompassing residues from Pro-18 to Arg-62 of into a four-stranded beta-domain that sequesters the helical YXXXXLPhi motif into a buried beta-strand, blocking accessibility to EIF4E. Protein phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize the fold, decreasing affinity for EIF4E by a factor of 4000 (PubMed:24207126, PubMed:25533957).2 Publications

Sequence similaritiesi

Belongs to the eIF4E-binding protein family.Curated

Phylogenomic databases

eggNOGiENOG410J2Z0. Eukaryota.
ENOG4112779. LUCA.
GeneTreeiENSGT00390000013843.
HOGENOMiHOG000231190.
HOVERGENiHBG050425.
InParanoidiQ13542.
KOiK18644.
OMAiVGDEAQF.
OrthoDBiEOG7B31Q1.
PhylomeDBiQ13542.
TreeFamiTF101530.

Family and domain databases

InterProiIPR008606. EIF4EBP.
[Graphical view]
PfamiPF05456. eIF_4EBP. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q13542-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSSSAGSGHQ PSQSRAIPTR TVAISDAAQL PHDYCTTPGG TLFSTTPGGT
60 70 80 90 100
RIIYDRKFLL DRRNSPMAQT PPCHLPNIPG VTSPGTLIED SKVEVNNLNN
110 120
LNNHDRKHAV GDDAQFEMDI
Length:120
Mass (Da):12,939
Last modified:November 1, 1996 - v1
Checksum:iB8F109261A504193
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L36056 mRNA. Translation: AAA62270.1.
BT007317 mRNA. Translation: AAP35981.1.
BC005057 mRNA. Translation: AAH05057.1.
BC050633 mRNA. Translation: AAH50633.1.
CCDSiCCDS7303.1.
PIRiS50867.
RefSeqiNP_004087.1. NM_004096.4.
UniGeneiHs.621200.
Hs.730236.

Genome annotation databases

EnsembliENST00000373218; ENSP00000362314; ENSG00000148730.
GeneIDi1979.
KEGGihsa:1979.
UCSCiuc001jrb.4. human.

Cross-referencesi

Web resourcesi

Protein Spotlight

A question of perspective - Issue 168 of April 2015

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L36056 mRNA. Translation: AAA62270.1.
BT007317 mRNA. Translation: AAP35981.1.
BC005057 mRNA. Translation: AAH05057.1.
BC050633 mRNA. Translation: AAH50633.1.
CCDSiCCDS7303.1.
PIRiS50867.
RefSeqiNP_004087.1. NM_004096.4.
UniGeneiHs.621200.
Hs.730236.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2MX4NMR-A18-62[»]
3AM7X-ray2.20B47-65[»]
ProteinModelPortaliQ13542.
SMRiQ13542. Positions 18-62.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108294. 12 interactions.
DIPiDIP-36572N.
IntActiQ13542. 3 interactions.
MINTiMINT-1510996.
STRINGi9606.ENSP00000362314.

PTM databases

iPTMnetiQ13542.
PhosphoSiteiQ13542.

Polymorphism and mutation databases

BioMutaiEIF4EBP2.
DMDMi34921510.

Proteomic databases

EPDiQ13542.
MaxQBiQ13542.
PaxDbiQ13542.
PeptideAtlasiQ13542.
PRIDEiQ13542.

Protocols and materials databases

DNASUi1979.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000373218; ENSP00000362314; ENSG00000148730.
GeneIDi1979.
KEGGihsa:1979.
UCSCiuc001jrb.4. human.

Organism-specific databases

CTDi1979.
GeneCardsiEIF4EBP2.
H-InvDBHIX0035538.
HGNCiHGNC:3289. EIF4EBP2.
HPAiCAB019415.
HPA037410.
HPA061665.
MIMi602224. gene.
neXtProtiNX_Q13542.
PharmGKBiPA27716.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410J2Z0. Eukaryota.
ENOG4112779. LUCA.
GeneTreeiENSGT00390000013843.
HOGENOMiHOG000231190.
HOVERGENiHBG050425.
InParanoidiQ13542.
KOiK18644.
OMAiVGDEAQF.
OrthoDBiEOG7B31Q1.
PhylomeDBiQ13542.
TreeFamiTF101530.

Miscellaneous databases

ChiTaRSiEIF4EBP2. human.
GeneWikiiEIF4EBP2.
GenomeRNAii1979.
NextBioi8007.
PROiQ13542.
SOURCEiSearch...

Gene expression databases

BgeeiQ13542.
CleanExiHS_EIF4EBP2.
ExpressionAtlasiQ13542. baseline and differential.
GenevisibleiQ13542. HS.

Family and domain databases

InterProiIPR008606. EIF4EBP.
[Graphical view]
PfamiPF05456. eIF_4EBP. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function."
    Pause A., Belsham G.J., Gingras A.-C., Donze O., Lin T.-A., Lawrence J.C. Jr., Sonenberg N.
    Nature 371:762-767(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH EIF4E.
    Tissue: Placenta.
  2. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
    Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
    Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: LungImported and UterusImported.
  4. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37 AND THR-46, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  5. "Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
    Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
    Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  6. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
    Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
    Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Leukemic T-cell.
  7. "Interaction of the eukaryotic initiation factor 4E with 4E-BP2 at a dynamic bipartite interface."
    Lukhele S., Bah A., Lin H., Sonenberg N., Forman-Kay J.D.
    Structure 21:2186-2196(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: DOMAIN, INTERACTION WITH EIF4E, MUTAGENESIS OF 54-TYR--LEU-59.
  8. "Structural scaffold for eIF4E binding selectivity of 4E-BP isoforms: crystal structure of eIF4E binding region of 4E-BP2 and its comparison with that of 4E-BP1."
    Fukuyo A., In Y., Ishida T., Tomoo K.
    J. Pept. Sci. 17:650-657(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 47-65 IN COMPLEX WITH EIF4E, INTERACTION WITH EIF4E, PHOSPHORYLATION.
  9. "Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch."
    Bah A., Vernon R.M., Siddiqui Z., Krzeminski M., Muhandiram R., Zhao C., Sonenberg N., Kay L.E., Forman-Kay J.D.
    Nature 519:106-109(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR OF 18-62, PHOSPHORYLATION AT THR-37; THR-46; SER-65; THR-70 AND SER-83, DOMAIN, FUNCTION, INTERACTION WITH EIF4E, MUTAGENESIS OF THR-37; GLY-39; THR-46 AND GLY-48.

Entry informationi

Entry namei4EBP2_HUMAN
AccessioniPrimary (citable) accession number: Q13542
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 19, 2003
Last sequence update: November 1, 1996
Last modified: May 11, 2016
This is version 130 of the entry and version 1 of the sequence. [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 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
  5. SIMILARITY comments
    Index of protein domains and families

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.