4EBP2_HUMAN
ID 4EBP2_HUMAN Reviewed; 120 AA.
AC Q13542;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Eukaryotic translation initiation factor 4E-binding protein 2 {ECO:0000303|PubMed:7935836};
DE Short=4E-BP2 {ECO:0000303|PubMed:7935836};
DE Short=eIF4E-binding protein 2 {ECO:0000303|PubMed:7935836};
GN Name=EIF4EBP2 {ECO:0000312|HGNC:HGNC:3289};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AAH05057.1};
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH EIF4E.
RC TISSUE=Placenta;
RX PubMed=7935836; DOI=10.1038/371762a0;
RA Pause A., Belsham G.J., Gingras A.-C., Donze O., Lin T.-A.,
RA Lawrence J.C. Jr., Sonenberg N.;
RT "Insulin-dependent stimulation of protein synthesis by phosphorylation of a
RT regulator of 5'-cap function.";
RL Nature 371:762-767(1994).
RN [2] {ECO:0000312|EMBL:AAP35981.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3] {ECO:0000312|EMBL:AAH05057.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung {ECO:0000312|EMBL:AAH05057.1}, and
RC Uterus {ECO:0000312|EMBL:AAH50633.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37 AND THR-46, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [8]
RP DOMAIN, INTERACTION WITH EIF4E, AND MUTAGENESIS OF 54-TYR--LEU-59.
RX PubMed=24207126; DOI=10.1016/j.str.2013.08.030;
RA Lukhele S., Bah A., Lin H., Sonenberg N., Forman-Kay J.D.;
RT "Interaction of the eukaryotic initiation factor 4E with 4E-BP2 at a
RT dynamic bipartite interface.";
RL Structure 21:2186-2196(2013).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 47-65 IN COMPLEX WITH EIF4E,
RP INTERACTION WITH EIF4E, AND PHOSPHORYLATION.
RX PubMed=21661078; DOI=10.1002/psc.1384;
RA Fukuyo A., In Y., Ishida T., Tomoo K.;
RT "Structural scaffold for eIF4E binding selectivity of 4E-BP isoforms:
RT crystal structure of eIF4E binding region of 4E-BP2 and its comparison with
RT that of 4E-BP1.";
RL J. Pept. Sci. 17:650-657(2011).
RN [10]
RP STRUCTURE BY NMR OF 18-62, PHOSPHORYLATION AT THR-37; THR-46; SER-65;
RP THR-70 AND SER-83, DOMAIN, FUNCTION, INTERACTION WITH EIF4E, AND
RP MUTAGENESIS OF THR-37; GLY-39; THR-46 AND GLY-48.
RX PubMed=25533957; DOI=10.1038/nature13999;
RA Bah A., Vernon R.M., Siddiqui Z., Krzeminski M., Muhandiram R., Zhao C.,
RA Sonenberg N., Kay L.E., Forman-Kay J.D.;
RT "Folding of an intrinsically disordered protein by phosphorylation as a
RT regulatory switch.";
RL Nature 519:106-109(2015).
CC -!- FUNCTION: Repressor of translation initiation involved in synaptic
CC plasticity, learning and memory formation (By similarity). Regulates
CC EIF4E activity by preventing its assembly into the eIF4F complex:
CC hypophosphorylated form of EIF4EBP2 competes with EIF4G1/EIF4G3 and
CC strongly binds to EIF4E, leading to repress translation. In contrast,
CC hyperphosphorylated form dissociates from EIF4E, allowing interaction
CC between EIF4G1/EIF4G3 and EIF4E, leading to initiation of translation
CC (PubMed:25533957). EIF4EBP2 is enriched in brain and acts as a
CC regulator of synapse activity and neuronal stem cell renewal via its
CC ability to repress translation initiation (By similarity). Mediates the
CC regulation of protein translation by hormones, growth factors and other
CC stimuli that signal through the MAP kinase and mTORC1 pathways (By
CC similarity). {ECO:0000250|UniProtKB:P70445,
CC ECO:0000269|PubMed:25533957}.
CC -!- SUBUNIT: Hypophosphorylated EIF4EBP2 interacts with EIF4E;
CC phosphorylation of EIF4EBP2 by mTORC1 causes dissociation of the
CC complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of
CC translation (PubMed:7935836, PubMed:24207126, PubMed:21661078,
CC PubMed:25533957). Interacts with RPTOR; promoting phosphorylation by
CC mTORC1 (By similarity). Interacts with PCMT1; required to prevent
CC isoaspartate accumulation and convert isoaspartate to Asp (By
CC similarity). {ECO:0000250|UniProtKB:P70445,
CC ECO:0000269|PubMed:21661078, ECO:0000269|PubMed:24207126,
CC ECO:0000269|PubMed:25533957, ECO:0000269|PubMed:7935836}.
CC -!- INTERACTION:
CC Q13542; P06730: EIF4E; NbExp=13; IntAct=EBI-935137, EBI-73440;
CC -!- DOMAIN: The TOS motif mediates interaction with RPTOR, leading to
CC promote phosphorylation by mTORC1 complex.
CC {ECO:0000250|UniProtKB:Q13541}.
CC -!- DOMAIN: Intrinsically disordered protein that undergoes folding upon
CC phosphorylation (PubMed:25533957). Hypophosphorylated form interacts
CC strongly with EIF4E using (1) the YXXXXLPhi motif, that undergoes a
CC disorder-to-helix transition upon binding and (2) the secondary EIF4E
CC binding sites (residues 78-82) (PubMed:24207126, PubMed:25533957).
CC Phosphorylation at Thr-37 and Thr-46 induces folding of region
CC encompassing residues from Pro-18 to Arg-62 of into a four-stranded
CC beta-domain that sequesters the helical YXXXXLPhi motif into a buried
CC beta-strand, blocking accessibility to EIF4E. Protein phosphorylated at
CC Thr-37 and Thr-46 is however unstable and subsequent phosphorylation at
CC Ser-65, Thr-70 and Ser-83 is required to stabilize the fold, decreasing
CC affinity for EIF4E by a factor of 4000 (PubMed:24207126,
CC PubMed:25533957). {ECO:0000269|PubMed:24207126,
CC ECO:0000269|PubMed:25533957}.
CC -!- PTM: Phosphorylation at Thr-37, Thr-46, Ser-65, Thr-70 and Ser-83 is
CC mediated by MTOR and corresponds to the hyperphosphorylated form: it
CC abolishes binding to EIF4E by inducing folding of intrinsically
CC disordered regions (PubMed:24207126, PubMed:25533957). First
CC phosphorylated at Thr-37 and Thr-46 by MTOR, inducing folding of region
CC encompassing residues from Pro-18 to Arg-62 of into a four-stranded
CC beta-domain that sequesters the helical YXXXXLPhi motif into a partly
CC buried beta-strand, blocking accessibility to EIF4E. Protein
CC phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent
CC phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize
CC the fold, decreasing affinity for EIF4E by a factor of 4000
CC (PubMed:24207126, PubMed:25533957). Phosphorylated in response to
CC insulin, EGF and PDGF. {ECO:0000269|PubMed:21661078,
CC ECO:0000269|PubMed:24207126, ECO:0000269|PubMed:25533957}.
CC -!- PTM: Deamidated at Asn-99 and Asn-102 to aspartate (Asp) in brain.
CC Deamidation promotes interaction with RPTOR, subsequent phosphorylation
CC by mTORC1 and increased translation, leading to impair kinetics of
CC excitatory synaptic transmission. Deamidation takes place during
CC postnatal development, when the PI3K-Akt-mTOR signaling is reduced,
CC suggesting it acts as a compensatory mechanism to promote translation
CC despite attenuated PI3K-Akt-mTOR signaling in neuron development.
CC Deamidation converts Asn residues into a mixture of Asp and
CC isoaspartate; interactions with PCMT1 is required to prevent
CC isoaspartate accumulation and convert isoaspartate to Asp.
CC {ECO:0000250|UniProtKB:P70445}.
CC -!- SIMILARITY: Belongs to the eIF4E-binding protein family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=A question of perspective
CC - Issue 168 of April 2015;
CC URL="https://web.expasy.org/spotlight/back_issues/168/";
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DR EMBL; L36056; AAA62270.1; -; mRNA.
DR EMBL; BT007317; AAP35981.1; -; mRNA.
DR EMBL; BC005057; AAH05057.1; -; mRNA.
DR EMBL; BC050633; AAH50633.1; -; mRNA.
DR CCDS; CCDS7303.1; -.
DR PIR; S50867; S50867.
DR RefSeq; NP_004087.1; NM_004096.4.
DR PDB; 2MX4; NMR; -; A=18-62.
DR PDB; 3AM7; X-ray; 2.20 A; B=47-65.
DR PDBsum; 2MX4; -.
DR PDBsum; 3AM7; -.
DR AlphaFoldDB; Q13542; -.
DR BMRB; Q13542; -.
DR SMR; Q13542; -.
DR BioGRID; 108294; 34.
DR DIP; DIP-36572N; -.
DR ELM; Q13542; -.
DR IntAct; Q13542; 6.
DR MINT; Q13542; -.
DR STRING; 9606.ENSP00000362314; -.
DR GlyGen; Q13542; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q13542; -.
DR MetOSite; Q13542; -.
DR PhosphoSitePlus; Q13542; -.
DR BioMuta; EIF4EBP2; -.
DR DMDM; 34921510; -.
DR EPD; Q13542; -.
DR jPOST; Q13542; -.
DR MassIVE; Q13542; -.
DR MaxQB; Q13542; -.
DR PaxDb; Q13542; -.
DR PeptideAtlas; Q13542; -.
DR PRIDE; Q13542; -.
DR ProteomicsDB; 59526; -.
DR Antibodypedia; 29025; 289 antibodies from 29 providers.
DR DNASU; 1979; -.
DR Ensembl; ENST00000373218.5; ENSP00000362314.4; ENSG00000148730.7.
DR GeneID; 1979; -.
DR KEGG; hsa:1979; -.
DR MANE-Select; ENST00000373218.5; ENSP00000362314.4; NM_004096.5; NP_004087.1.
DR UCSC; uc001jrb.4; human.
DR CTD; 1979; -.
DR DisGeNET; 1979; -.
DR GeneCards; EIF4EBP2; -.
DR HGNC; HGNC:3289; EIF4EBP2.
DR HPA; ENSG00000148730; Low tissue specificity.
DR MIM; 602224; gene.
DR neXtProt; NX_Q13542; -.
DR OpenTargets; ENSG00000148730; -.
DR PharmGKB; PA27716; -.
DR VEuPathDB; HostDB:ENSG00000148730; -.
DR eggNOG; ENOG502S44S; Eukaryota.
DR GeneTree; ENSGT00940000155342; -.
DR HOGENOM; CLU_111706_0_0_1; -.
DR InParanoid; Q13542; -.
DR OMA; NHINNRD; -.
DR OrthoDB; 1597535at2759; -.
DR PhylomeDB; Q13542; -.
DR TreeFam; TF101530; -.
DR PathwayCommons; Q13542; -.
DR SignaLink; Q13542; -.
DR SIGNOR; Q13542; -.
DR BioGRID-ORCS; 1979; 18 hits in 1068 CRISPR screens.
DR ChiTaRS; EIF4EBP2; human.
DR GeneWiki; EIF4EBP2; -.
DR GenomeRNAi; 1979; -.
DR Pharos; Q13542; Tbio.
DR PRO; PR:Q13542; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q13542; protein.
DR Bgee; ENSG00000148730; Expressed in buccal mucosa cell and 214 other tissues.
DR ExpressionAtlas; Q13542; baseline and differential.
DR Genevisible; Q13542; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; ISS:UniProtKB.
DR GO; GO:0030371; F:translation repressor activity; ISS:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007613; P:memory; ISS:UniProtKB.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; ISS:UniProtKB.
DR GO; GO:0045947; P:negative regulation of translational initiation; ISS:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0035176; P:social behavior; ISS:UniProtKB.
DR GO; GO:0031929; P:TOR signaling; ISS:UniProtKB.
DR GO; GO:0006412; P:translation; TAS:ProtInc.
DR DisProt; DP01293; -.
DR IDEAL; IID00564; -.
DR InterPro; IPR008606; EIF4EBP.
DR Pfam; PF05456; eIF_4EBP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Phosphoprotein; Protein synthesis inhibitor;
KW Reference proteome; Translation regulation.
FT CHAIN 1..120
FT /note="Eukaryotic translation initiation factor 4E-binding
FT protein 2"
FT /id="PRO_0000190516"
FT REGION 1..48
FT /note="Disordered"
FT /evidence="ECO:0000305|PubMed:24207126,
FT ECO:0000305|PubMed:25533957"
FT REGION 65..120
FT /note="Disordered"
FT /evidence="ECO:0000305|PubMed:24207126,
FT ECO:0000305|PubMed:25533957"
FT MOTIF 54..60
FT /note="YXXXXLphi motif"
FT /evidence="ECO:0000269|PubMed:24207126,
FT ECO:0000269|PubMed:25533957"
FT MOTIF 78..82
FT /note="Secondary EIF4E binding site"
FT /evidence="ECO:0000269|PubMed:24207126,
FT ECO:0000269|PubMed:25533957"
FT MOTIF 116..120
FT /note="TOS motif"
FT /evidence="ECO:0000250|UniProtKB:Q13541"
FT MOD_RES 37
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:25533957,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332"
FT MOD_RES 46
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:25533957,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 65
FT /note="Phosphoserine; by MTOR"
FT /evidence="ECO:0000269|PubMed:25533957"
FT MOD_RES 70
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:25533957"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:25533957"
FT MOD_RES 99
FT /note="Deamidated asparagine"
FT /evidence="ECO:0000250|UniProtKB:P70445"
FT MOD_RES 102
FT /note="Deamidated asparagine"
FT /evidence="ECO:0000250|UniProtKB:P70445"
FT MUTAGEN 37
FT /note="T->D,E: Acidic residues do not mimic phosphorylation
FT state. Does not induce folding of the intrinsically
FT disordered protein; when associated with D-46 or E-46."
FT /evidence="ECO:0000269|PubMed:25533957"
FT MUTAGEN 39
FT /note="G->V: Abolishes folding of the intrinsically
FT disordered protein without affecting greatly affinity for
FT EIF4E even when the protein is fully phosphorylated; when
FT associated with V-48."
FT /evidence="ECO:0000269|PubMed:25533957"
FT MUTAGEN 46
FT /note="T->D,E: Acidic residues do not mimic phosphorylation
FT state. Does not induce folding of the intrinsically
FT disordered protein; when associated with D-37 or E-37."
FT /evidence="ECO:0000269|PubMed:25533957"
FT MUTAGEN 48
FT /note="G->V: Abolishes folding of the intrinsically
FT disordered protein without affecting greatly affinity for
FT EIF4E even when the protein is fully phosphorylated; when
FT associated with V-39."
FT /evidence="ECO:0000269|PubMed:25533957"
FT MUTAGEN 54..60
FT /note="YDRKFLL->AAAAAAA: Impaired binding to EIF4E."
FT /evidence="ECO:0000269|PubMed:24207126"
FT MUTAGEN 78..82
FT /note="IPGVT->AAAAA: Impaired binding to EIF4E."
FT /evidence="ECO:0000269|PubMed:24207126"
FT STRAND 19..24
FT /evidence="ECO:0007829|PDB:2MX4"
FT TURN 27..29
FT /evidence="ECO:0007829|PDB:2MX4"
FT STRAND 42..45
FT /evidence="ECO:0007829|PDB:2MX4"
FT HELIX 56..60
FT /evidence="ECO:0007829|PDB:3AM7"
SQ SEQUENCE 120 AA; 12939 MW; B8F109261A504193 CRC64;
MSSSAGSGHQ PSQSRAIPTR TVAISDAAQL PHDYCTTPGG TLFSTTPGGT RIIYDRKFLL
DRRNSPMAQT PPCHLPNIPG VTSPGTLIED SKVEVNNLNN LNNHDRKHAV GDDAQFEMDI
