4EBP_DROME
ID 4EBP_DROME Reviewed; 117 AA.
AC Q9XZ56;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Eukaryotic translation initiation factor 4E-binding protein {ECO:0000305};
DE Short=4E-BP {ECO:0000303|PubMed:14645523, ECO:0000303|PubMed:19804760};
DE Short=d4E-BP {ECO:0000303|PubMed:14645523, ECO:0000303|PubMed:19804760};
DE Short=eIF4E-binding protein;
DE AltName: Full=4E-binding protein Thor {ECO:0000303|PubMed:10811906};
DE Short=dThor {ECO:0000303|PubMed:10811906};
GN Name=Thor {ECO:0000303|PubMed:10811906, ECO:0000312|FlyBase:FBgn0261560};
GN ORFNames=CG8846 {ECO:0000312|FlyBase:FBgn0261560};
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, TISSUE SPECIFICITY,
RP DEVELOPMENTAL STAGE, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=10811906; DOI=10.1073/pnas.100391597;
RA Bernal A., Kimbrell D.A.;
RT "Drosophila Thor participates in host immune defense and connects a
RT translational regulator with innate immunity.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:6019-6024(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley;
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3]
RP GENOME REANNOTATION.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Berkeley; TISSUE=Head;
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN [5]
RP FUNCTION, INTERACTION WITH EIF4E1, PHOSPHORYLATION, DOMAIN, AND MUTAGENESIS
RP OF TYR-54; 59-MET-LYS-60 AND LYS-60.
RX PubMed=11389445; DOI=10.1038/35078571;
RA Miron M., Verdu J., Lachance P.E., Birnbaum M.J., Lasko P.F., Sonenberg N.;
RT "The translational inhibitor 4E-BP is an effector of PI(3)K/Akt signalling
RT and cell growth in Drosophila.";
RL Nat. Cell Biol. 3:596-601(2001).
RN [6]
RP INTERACTION WITH EIF4E1, PHOSPHORYLATION AT THR-37 AND THR-46, AND
RP MUTAGENESIS OF THR-37 AND THR-46.
RX PubMed=14645523; DOI=10.1128/mcb.23.24.9117-9126.2003;
RA Miron M., Lasko P., Sonenberg N.;
RT "Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila
RT melanogaster.";
RL Mol. Cell. Biol. 23:9117-9126(2003).
RN [7]
RP FUNCTION.
RX PubMed=19804760; DOI=10.1016/j.cell.2009.07.034;
RA Zid B.M., Rogers A.N., Katewa S.D., Vargas M.A., Kolipinski M.C., Lu T.A.,
RA Benzer S., Kapahi P.;
RT "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial
RT activity in Drosophila.";
RL Cell 139:149-160(2009).
RN [8]
RP FUNCTION, AND INDUCTION.
RX PubMed=27525480; DOI=10.7554/elife.16807;
RA Mahoney R.E., Azpurua J., Eaton B.A.;
RT "Insulin signaling controls neurotransmission via the 4eBP-dependent
RT modification of the exocytotic machinery.";
RL Elife 5:0-0(2016).
RN [9]
RP FUNCTION, AND INDUCTION.
RX PubMed=27916456; DOI=10.1016/j.neuron.2016.10.063;
RA Kauwe G., Tsurudome K., Penney J., Mori M., Gray L., Calderon M.R.,
RA Elazouzzi F., Chicoine N., Sonenberg N., Haghighi A.P.;
RT "Acute fasting regulates retrograde synaptic enhancement through a 4E-BP-
RT dependent mechanism.";
RL Neuron 92:1204-1212(2016).
RN [10]
RP FUNCTION.
RX PubMed=28827349; DOI=10.1073/pnas.1618994114;
RA Carvalho G.B., Drago I., Hoxha S., Yamada R., Mahneva O., Bruce K.D.,
RA Soto Obando A., Conti B., Ja W.W.;
RT "The 4E-BP growth pathway regulates the effect of ambient temperature on
RT Drosophila metabolism and lifespan.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:9737-9742(2017).
RN [11] {ECO:0007744|PDB:4UE8}
RP X-RAY CRYSTALLOGRAPHY (1.10 ANGSTROMS) OF 50-83 IN COMPLEX WITH EIF4E1,
RP FUNCTION, INTERACTION WITH EIF4E1, PHOSPHORYLATION AT SER-65 AND THR-70,
RP AND MUTAGENESIS OF 65-SER--THR-70.
RX PubMed=25702871; DOI=10.1016/j.molcel.2015.01.017;
RA Peter D., Igreja C., Weber R., Wohlbold L., Weiler C., Ebertsch L.,
RA Weichenrieder O., Izaurralde E.;
RT "Molecular architecture of 4E-BP translational inhibitors bound to eIF4E.";
RL Mol. Cell 57:1074-1087(2015).
CC -!- FUNCTION: Repressor of translation initiation that regulates eIF4E1
CC activity by preventing its assembly into the eIF4F complex
CC (PubMed:11389445, PubMed:19804760, PubMed:25702871). Hypophosphorylated
CC form competes with eIF4G1 and strongly binds to eIF4E1, leading to
CC repress translation (PubMed:25702871). In contrast, hyperphosphorylated
CC form dissociates from eIF4E1, allowing interaction between eIF4G1 and
CC eIF4E1, leading to initiation of translation (PubMed:25702871). Acts as
CC a regulator of various biological processes, such as innate immunity,
CC cell growth or synaptic transmission (PubMed:10811906, PubMed:11389445,
CC PubMed:27525480). Acts downstream of phosphoinositide-3-kinase (PI3K)
CC to regulate cell growth (PubMed:11389445). Extends lifespan upon
CC dietary restriction by regulating the mitochondrial translation
CC (PubMed:19804760). Acts as a regulator of lifespan in response to cold
CC by regulating the mitochondrial translation (PubMed:28827349). Acts as
CC a negative regulator of presynaptic release of neurotransmitter in
CC motor neurons: Thor expression is induced in response to insulin
CC signaling, leading to prevent of translation of complexin (cpx), a
CC protein known to regulate the exocytosis of synaptic vesicles
CC (PubMed:27525480). Acts as a negative regulator of synaptic strength at
CC the neuromuscular junction: Thor expression in response to acute
CC fasting prevents translation, thereby suppressing retrograde synaptic
CC enhancement (PubMed:27916456). {ECO:0000269|PubMed:10811906,
CC ECO:0000269|PubMed:11389445, ECO:0000269|PubMed:19804760,
CC ECO:0000269|PubMed:25702871, ECO:0000269|PubMed:27525480,
CC ECO:0000269|PubMed:27916456, ECO:0000269|PubMed:28827349}.
CC -!- SUBUNIT: Hypophosphorylated Thor/4E-BP competes with eIF4G1 to interact
CC with eIF4E1; insulin stimulated Akt1 or Tor phosphorylation of Thor/4E-
CC BP causes dissociation of the complex allowing eIF4G1 to bind and
CC consequent initiation of translation. {ECO:0000269|PubMed:11389445,
CC ECO:0000269|PubMed:14645523}.
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:10811906}.
CC -!- DEVELOPMENTAL STAGE: Expressed during all developmental stages.
CC {ECO:0000269|PubMed:10811906}.
CC -!- INDUCTION: Up-regulated in response to bacterial infection
CC (PubMed:10811906). Expression is induced by foxo: in neurons, foxo-
CC dependent expression is activated in response to insulin signaling,
CC while in muscle foxo-dependent expression is activated in response to
CC fasting (PubMed:27525480, PubMed:27916456).
CC {ECO:0000269|PubMed:10811906, ECO:0000269|PubMed:27525480,
CC ECO:0000269|PubMed:27916456}.
CC -!- DOMAIN: The YXXXXLphi motif mediates interaction with eIF4E1
CC (PubMed:11389445). Compared to other members of the family this
CC YXXXXLphi is atypical and interaction with eIF4E1 is weaker
CC (PubMed:11389445). {ECO:0000269|PubMed:11389445}.
CC -!- PTM: Phosphorylation at Thr-37, Thr-46, Ser-65 and Thr-70,
CC corresponding to the hyperphosphorylated form, impairs its ability to
CC prevent the interaction between eIF4G1 and eIF4E1, without affecting
CC its interaction with free eIF4E1 (PubMed:14645523, PubMed:25702871).
CC Phosphorylated in rtesponse to insulin (PubMed:11389445).
CC Phosphorylation at Thr-46 is regulated by Tor and constitutes the major
CC phosphorylation event that regulates activity (PubMed:14645523).
CC {ECO:0000269|PubMed:11389445, ECO:0000269|PubMed:14645523,
CC ECO:0000269|PubMed:25702871}.
CC -!- DISRUPTION PHENOTYPE: Impaired innate immune response.
CC {ECO:0000269|PubMed:10811906}.
CC -!- SIMILARITY: Belongs to the eIF4E-binding protein family. {ECO:0000305}.
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DR EMBL; AF244353; AAF82476.1; -; Genomic_DNA.
DR EMBL; AE014134; AAF51100.1; -; Genomic_DNA.
DR EMBL; AE014134; AHN54103.1; -; Genomic_DNA.
DR EMBL; AF132557; AAD27856.1; -; mRNA.
DR RefSeq; NP_001285588.1; NM_001298659.1.
DR RefSeq; NP_477295.1; NM_057947.4.
DR PDB; 4UE8; X-ray; 1.10 A; B=50-83.
DR PDBsum; 4UE8; -.
DR AlphaFoldDB; Q9XZ56; -.
DR SMR; Q9XZ56; -.
DR IntAct; Q9XZ56; 227.
DR STRING; 7227.FBpp0077213; -.
DR PaxDb; Q9XZ56; -.
DR EnsemblMetazoa; FBtr0077524; FBpp0077213; FBgn0261560.
DR EnsemblMetazoa; FBtr0345289; FBpp0311456; FBgn0261560.
DR GeneID; 33569; -.
DR KEGG; dme:Dmel_CG8846; -.
DR UCSC; CG8846-RA; d. melanogaster.
DR CTD; 33569; -.
DR FlyBase; FBgn0261560; Thor.
DR VEuPathDB; VectorBase:FBgn0261560; -.
DR eggNOG; ENOG502S44S; Eukaryota.
DR GeneTree; ENSGT00940000171059; -.
DR HOGENOM; CLU_111706_1_0_1; -.
DR InParanoid; Q9XZ56; -.
DR OMA; PMMTRKI; -.
DR OrthoDB; 1597535at2759; -.
DR PhylomeDB; Q9XZ56; -.
DR Reactome; R-DME-110523; TOR signaling pathway.
DR Reactome; R-DME-166208; mTORC1-mediated signalling.
DR Reactome; R-DME-72662; Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S.
DR SignaLink; Q9XZ56; -.
DR BioGRID-ORCS; 33569; 0 hits in 3 CRISPR screens.
DR ChiTaRS; Thor; fly.
DR GenomeRNAi; 33569; -.
DR Proteomes; UP000000803; Chromosome 2L.
DR Bgee; FBgn0261560; Expressed in spermathecum and 60 other tissues.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:FlyBase.
DR GO; GO:0098978; C:glutamatergic synapse; IMP:SynGO.
DR GO; GO:0031594; C:neuromuscular junction; IMP:SynGO.
DR GO; GO:0098793; C:presynapse; IEA:GOC.
DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; IDA:FlyBase.
DR GO; GO:0045182; F:translation regulator activity; IMP:SynGO.
DR GO; GO:0019731; P:antibacterial humoral response; IMP:FlyBase.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:FlyBase.
DR GO; GO:0034599; P:cellular response to oxidative stress; IGI:FlyBase.
DR GO; GO:0008340; P:determination of adult lifespan; IDA:FlyBase.
DR GO; GO:0006955; P:immune response; IMP:FlyBase.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:FlyBase.
DR GO; GO:0045792; P:negative regulation of cell size; IMP:FlyBase.
DR GO; GO:1905536; P:negative regulation of eukaryotic translation initiation factor 4F complex assembly; IDA:FlyBase.
DR GO; GO:0045947; P:negative regulation of translational initiation; IDA:FlyBase.
DR GO; GO:0001558; P:regulation of cell growth; IMP:FlyBase.
DR GO; GO:0070129; P:regulation of mitochondrial translation; IDA:FlyBase.
DR GO; GO:2000331; P:regulation of terminal button organization; IMP:FlyBase.
DR GO; GO:0099577; P:regulation of translation at presynapse, modulating synaptic transmission; IMP:SynGO.
DR GO; GO:0009617; P:response to bacterium; IDA:FlyBase.
DR GO; GO:0006979; P:response to oxidative stress; IMP:FlyBase.
DR GO; GO:0042594; P:response to starvation; IDA:FlyBase.
DR GO; GO:0006641; P:triglyceride metabolic process; IMP:FlyBase.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IDA:FlyBase.
DR InterPro; IPR008606; EIF4EBP.
DR Pfam; PF05456; eIF_4EBP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Immunity; Innate immunity; Phosphoprotein;
KW Protein synthesis inhibitor; Reference proteome; Translation regulation.
FT CHAIN 1..117
FT /note="Eukaryotic translation initiation factor 4E-binding
FT protein"
FT /id="PRO_0000450889"
FT MOTIF 54..60
FT /note="YXXXXLphi motif; atypical"
FT /evidence="ECO:0000269|PubMed:11389445"
FT MOD_RES 37
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:14645523"
FT MOD_RES 46
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:14645523"
FT MOD_RES 65
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:25702871"
FT MOD_RES 70
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:25702871"
FT MUTAGEN 37
FT /note="T->A: Decreased phosphorylation in response."
FT /evidence="ECO:0000269|PubMed:14645523"
FT MUTAGEN 46
FT /note="T->A: Decreased phosphorylation in response."
FT /evidence="ECO:0000269|PubMed:14645523"
FT MUTAGEN 54
FT /note="Y->E,F: Abolished interaction with eIF4E1."
FT /evidence="ECO:0000269|PubMed:11389445"
FT MUTAGEN 59..60
FT /note="MK->LL: In d4E-BP(LL) mutant; increased interaction
FT with eIF4E1; expression of this mutant in wing-imaginal
FT disks causes a reduction of wing size, caused by a decrease
FT in cell size and number."
FT /evidence="ECO:0000269|PubMed:11389445"
FT MUTAGEN 60
FT /note="K->A: Strongly decreased interaction with eIF4E1."
FT /evidence="ECO:0000269|PubMed:11389445"
FT MUTAGEN 65..70
FT /note="SPLSQT->DPLSQD: Phosphomimetic mutant; does not
FT affect interaction with free eIF4E1."
FT /evidence="ECO:0000269|PubMed:25702871"
FT HELIX 56..60
FT /evidence="ECO:0007829|PDB:4UE8"
FT TURN 61..64
FT /evidence="ECO:0007829|PDB:4UE8"
FT HELIX 66..68
FT /evidence="ECO:0007829|PDB:4UE8"
FT HELIX 77..79
FT /evidence="ECO:0007829|PDB:4UE8"
SQ SEQUENCE 117 AA; 12876 MW; 8A2CD2D318124CA0 CRC64;
MSASPTARQA ITQALPMITR KVVISDPIQM PEVYSSTPGG TLYSTTPGGT KLIYERAFMK
NLRGSPLSQT PPSNVPSCLL RGTPRTPFRK CVPVPTELIK QTKSLKIEDQ EQFQLDL
