Full text data of EIF4G1
EIF4G1
(EIF4F, EIF4G, EIF4GI)
[Confidence: low (only semi-automatic identification from reviews)]
Eukaryotic translation initiation factor 4 gamma 1; eIF-4-gamma 1; eIF-4G 1; eIF-4G1 (p220)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Eukaryotic translation initiation factor 4 gamma 1; eIF-4-gamma 1; eIF-4G 1; eIF-4G1 (p220)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q04637
ID IF4G1_HUMAN Reviewed; 1599 AA.
AC Q04637; D3DNT2; D3DNT4; D3DNT5; E9PFM1; G5E9S1; O43177; O95066;
read moreAC Q5HYG0; Q6ZN21; Q8N102;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 4.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Eukaryotic translation initiation factor 4 gamma 1;
DE Short=eIF-4-gamma 1;
DE Short=eIF-4G 1;
DE Short=eIF-4G1;
DE AltName: Full=p220;
GN Name=EIF4G1; Synonyms=EIF4F, EIF4G, EIF4GI;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND VARIANT VAL-432.
RC TISSUE=Brain;
RX PubMed=1429670;
RA Yan R., Rychlik W., Etchison D., Rhoads R.E.;
RT "Amino acid sequence of the human protein synthesis initiation factor
RT eIF-4 gamma.";
RL J. Biol. Chem. 267:23226-23231(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND INTERACTION WITH PABPC1.
RX PubMed=9857202; DOI=10.1093/emboj/17.24.7480;
RA Imataka H., Gradi A., Sonenberg N.;
RT "A newly identified N-terminal amino acid sequence of human eIF4G
RT binds poly(A)-binding protein and functions in poly(A)-dependent
RT translation.";
RL EMBO J. 17:7480-7489(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM C).
RX PubMed=9418880;
RA Gradi A., Imataka H., Svitkin Y.V., Rom E., Raught B., Morino S.,
RA Sonenberg N.;
RT "A novel functional human eukaryotic translation initiation factor
RT 4G.";
RL Mol. Cell. Biol. 18:334-342(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), VARIANTS ALA-161 AND VAL-432,
RP AND ALTERNATIVE INITIATION.
RX PubMed=12052860; DOI=10.1128/MCB.22.13.4499-4511.2002;
RA Byrd M.P., Zamora M., Lloyd R.E.;
RT "Generation of multiple isoforms of eukaryotic translation initiation
RT factor 4GI by use of alternate translation initiation codons.";
RL Mol. Cell. Biol. 22:4499-4511(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A), AND VARIANT
RP ALA-161.
RC TISSUE=Endometrial tumor;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-206, NUCLEOTIDE SEQUENCE [GENOMIC
RP DNA] OF 180-234, VARIANT ALA-161, AND INTERACTION WITH ROTAVIRAL NSP3.
RX PubMed=9755181; DOI=10.1093/emboj/17.19.5811;
RA Piron M., Vende P., Cohen J., Poncet D.;
RT "Rotavirus RNA binding protein NSP3, interacts with eIF-4GI and evicts
RT the poly(A) binding protein from eIF4F.";
RL EMBO J. 17:5811-5821(1998).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-1599 (ISOFORM 8), INTERACTION WITH
RP EIF4A, VARIANTS ALA-161 AND VAL-432, AND MUTAGENESIS OF LEU-768;
RP LEU-771; PHE-776; 842-LEU-LEU-843; 851-PHE-GLU-852; LEU-896; ILE-902;
RP LEU-905; ARG-974; PHE-977; LEU-985 AND TRP-990.
RX PubMed=9372926;
RA Imataka H., Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) possesses
RT two separate and independent binding sites for eIF4A.";
RL Mol. Cell. Biol. 17:6940-6947(1997).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 605-721, INTERACTION WITH EIF4E, AND
RP MUTAGENESIS OF TYR-612 AND 617-LEU-LEU-618.
RX PubMed=7651417;
RA Mader S., Lee H., Pause A., Sonenberg N.;
RT "The translation initiation factor eIF-4E binds to a common motif
RT shared by the translation factor eIF-4 gamma and the translational
RT repressors 4E-binding proteins.";
RL Mol. Cell. Biol. 15:4990-4997(1995).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 682-912 (ISOFORM 8).
RA De Gregorio E.;
RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP CLEAVAGE BY RHINOVIRUS AND COXSACKIEVIRUS PROTEASE.
RX PubMed=8396129;
RA Lamphear B.J., Yan R., Yang F., Waters D., Liebig H.-D., Klump H.,
RA Kuechler E., Skern T., Rhoads R.E.;
RT "Mapping the cleavage site in protein synthesis initiation factor eIF-
RT 4 gamma of the 2A proteases from human Coxsackievirus and
RT rhinovirus.";
RL J. Biol. Chem. 268:19200-19203(1993).
RN [14]
RP 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
RT of a regulator of 5'-cap function.";
RL Nature 371:762-767(1994).
RN [15]
RP INTERACTION WITH EIF4E AND EIF4EBP1.
RX PubMed=8521827;
RA Haghighat A., Mader S., Pause A., Sonenberg N.;
RT "Repression of cap-dependent translation by 4E-binding protein 1:
RT competition with p220 for binding to eukaryotic initiation factor-
RT 4E.";
RL EMBO J. 14:5701-5709(1995).
RN [16]
RP MUTAGENESIS OF GLY-682.
RX PubMed=8961935; DOI=10.1021/bi961864t;
RA Lamphear B.J., Rhoads R.E.;
RT "A single amino acid change in protein synthesis initiation factor 4G
RT renders cap-dependent translation resistant to picornaviral 2A
RT proteases.";
RL Biochemistry 35:15726-15733(1996).
RN [17]
RP CLEAVAGE BY POLIOVIRUS.
RX PubMed=9755863; DOI=10.1016/S0014-5793(98)01027-8;
RA Ventoso I., MacMillan S.E., Hershey J.W., Carrasco L.;
RT "Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-
RT 4F complex.";
RL FEBS Lett. 435:79-83(1998).
RN [18]
RP REVIEW.
RX PubMed=10872469; DOI=10.1146/annurev.biochem.68.1.913;
RA Gingras A.-C., Raught B., Sonenberg N.;
RT "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes
RT and regulators of translation.";
RL Annu. Rev. Biochem. 68:913-963(1999).
RN [19]
RP INTERACTION WITH MKNK1.
RX PubMed=9878069; DOI=10.1093/emboj/18.1.270;
RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T.,
RA Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits
RT mnk1 to phosphorylate eIF4E.";
RL EMBO J. 18:270-279(1999).
RN [20]
RP INTERACTION WITH PABPC1, AND MUTAGENESIS OF 174-LYS--LYS-178 AND
RP 184-ASP--GLN-197.
RX PubMed=10996799; DOI=10.1016/S0960-9822(00)00701-6;
RA Wakiyama M., Imataka H., Sonenberg N.;
RT "Interaction of eIF4G with poly(A)-binding protein stimulates
RT translation and is critical for Xenopus oocyte maturation.";
RL Curr. Biol. 10:1147-1150(2000).
RN [21]
RP INTERACTION WITH PABPC1.
RX PubMed=10970864; DOI=10.1093/emboj/19.17.4723;
RA Gray N.K., Coller J.M., Dickson K.S., Wickens M.;
RT "Multiple portions of poly(A)-binding protein stimulate translation in
RT vivo.";
RL EMBO J. 19:4723-4733(2000).
RN [22]
RP CLEAVAGE BY FMDV AND HRV-2.
RX PubMed=11034318; DOI=10.1016/S0014-5793(00)01928-1;
RA Glaser W., Skern T.;
RT "Extremely efficient cleavage of eIF4G by picornaviral proteinases L
RT and 2A in vitro.";
RL FEBS Lett. 480:151-155(2000).
RN [23]
RP INTERACTION WITH MKNK2.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [26]
RP INTERACTION WITH CIRBP.
RX PubMed=16513844; DOI=10.1093/nar/gkj519;
RA Yang R., Weber D.J., Carrier F.;
RT "Post-transcriptional regulation of thioredoxin by the stress
RT inducible heterogeneous ribonucleoprotein A18.";
RL Nucleic Acids Res. 34:1224-1236(2006).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1092, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [28]
RP INTERACTION WITH RBM4.
RX PubMed=17284590; DOI=10.1073/pnas.0611015104;
RA Lin J.C., Hsu M., Tarn W.Y.;
RT "Cell stress modulates the function of splicing regulatory protein
RT RBM4 in translation control.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:2235-2240(2007).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [30]
RP INTERACTION WITH ROTAVIRUS A NSP3.
RX PubMed=18799579; DOI=10.1128/JVI.00872-08;
RA Harb M., Becker M.M., Vitour D., Baron C.H., Vende P., Brown S.C.,
RA Bolte S., Arold S.T., Poncet D.;
RT "Nuclear localization of cytoplasmic poly(A)-binding protein upon
RT rotavirus infection involves the interaction of NSP3 with eIF4G and
RT RoXaN.";
RL J. Virol. 82:11283-11293(2008).
RN [31]
RP INTERACTION WITH MIF4GD.
RX PubMed=18025107; DOI=10.1128/MCB.01500-07;
RA Cakmakci N.G., Lerner R.S., Wagner E.J., Zheng L., Marzluff W.F.;
RT "SLIP1, a factor required for activation of histone mRNA translation
RT by the stem-loop binding protein.";
RL Mol. Cell. Biol. 28:1182-1194(2008).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-223; THR-647;
RP SER-1092 AND SER-1209, AND MASS SPECTROMETRY.
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 [33]
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.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [35]
RP IDENTIFICATION BY 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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1095, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092;
RP SER-1185; SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [39]
RP PHOSPHORYLATION AT SER-1185.
RX PubMed=21576361; DOI=10.1128/MCB.05589-11;
RA Dobrikov M., Dobrikova E., Shveygert M., Gromeier M.;
RT "Phosphorylation of eukaryotic translation initiation factor 4G1
RT (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to
RT Mnk1.";
RL Mol. Cell. Biol. 31:2947-2959(2011).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092;
RP SER-1145; SER-1147; SER-1185; SER-1187; SER-1209; THR-1211; SER-1231
RP AND SER-1596, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.38 ANGSTROMS) OF 172-199 IN COMPLEX WITH
RP ROTAVIRAL NSP3, INTERACTION WITH PABPC1, AND MUTAGENESIS OF ILE-180;
RP ILE-182; ILE-192 AND ILE-196.
RX PubMed=12086624; DOI=10.1016/S1097-2765(02)00555-5;
RA Groft C.M., Burley S.K.;
RT "Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA
RT circularization.";
RL Mol. Cell 9:1273-1283(2002).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (2.24 ANGSTROMS) OF 1234-1571.
RX PubMed=16698552; DOI=10.1016/j.str.2006.03.012;
RA Bellsolell L., Cho-Park P.F., Poulin F., Sonenberg N., Burley S.K.;
RT "Two structurally atypical HEAT domains in the C-terminal portion of
RT human eIF4G support binding to eIF4A and Mnk1.";
RL Structure 14:913-923(2006).
RN [44]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-696.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [45]
RP VARIANTS PARK18 VAL-502 AND HIS-1205, AND VARIANTS SER-71; ALA-161;
RP CYS-311; VAL-432; 466-GLY--ALA-468 DEL; CYS-686; VAL-806; SER-829;
RP ARG-1164; TRP-1197; ALA-1229; PRO-1233 AND SER-1257.
RX PubMed=21907011; DOI=10.1016/j.ajhg.2011.08.009;
RA Chartier-Harlin M.C., Dachsel J.C., Vilarino-Guell C., Lincoln S.J.,
RA Lepretre F., Hulihan M.M., Kachergus J., Milnerwood A.J., Tapia L.,
RA Song M.S., Le Rhun E., Mutez E., Larvor L., Duflot A.,
RA Vanbesien-Mailliot C., Kreisler A., Ross O.A., Nishioka K.,
RA Soto-Ortolaza A.I., Cobb S.A., Melrose H.L., Behrouz B., Keeling B.H.,
RA Bacon J.A., Hentati E., Williams L., Yanagiya A., Sonenberg N.,
RA Lockhart P.J., Zubair A.C., Uitti R.J., Aasly J.O., Krygowska-Wajs A.,
RA Opala G., Wszolek Z.K., Frigerio R., Maraganore D.M., Gosal D.,
RA Lynch T., Hutchinson M., Bentivoglio A.R., Valente E.M., Nichols W.C.,
RA Pankratz N., Foroud T., Gibson R.A., Hentati F., Dickson D.W.,
RA Destee A., Farrer M.J.;
RT "Translation initiator EIF4G1 mutations in familial Parkinson
RT disease.";
RL Am. J. Hum. Genet. 89:398-406(2011).
CC -!- FUNCTION: Component of the protein complex eIF4F, which is
CC involved in the recognition of the mRNA cap, ATP-dependent
CC unwinding of 5'-terminal secondary structure and recruitment of
CC mRNA to the ribosome.
CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of
CC which varies with external and internal environmental conditions.
CC It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3.
CC Interacts with eIF3, mutually exclusive with EIF4A1 or EIFA2,
CC EIF4E and through its N-terminus with PAPBC1. Interacts through
CC its C-terminus with the serine/threonine kinases MKNK1, and with
CC MKNK2. Appears to act as a scaffold protein, holding these enzymes
CC in place to phosphorylate EIF4E. Non-phosphorylated EIF4EBP1
CC competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin
CC stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of
CC EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3
CC to bind and consequent initiation of translation. EIF4G1/EIF4G3
CC interacts with PABPC1 to bring about circularization of the mRNA.
CC Rapamycin can attenuate insulin stimulation mediated by FKBPs.
CC Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts
CC with rotavirus A NSP3; in this interaction, NSP3 takes the place
CC of PABPC1 thereby inducing shutoff of host protein synthesis.
CC Interacts with RBM4.
CC -!- INTERACTION:
CC O00571:DDX3X; NbExp=3; IntAct=EBI-73711, EBI-353779;
CC O75822:EIF3J; NbExp=2; IntAct=EBI-73711, EBI-366647;
CC P60842:EIF4A1; NbExp=7; IntAct=EBI-73711, EBI-73449;
CC P06730:EIF4E; NbExp=2; IntAct=EBI-73711, EBI-73440;
CC Q14103-4:HNRNPD; NbExp=3; IntAct=EBI-73711, EBI-432545;
CC P11940:PABPC1; NbExp=2; IntAct=EBI-73711, EBI-81531;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=8;
CC Name=A;
CC IsoId=Q04637-1; Sequence=Displayed;
CC Name=B;
CC IsoId=Q04637-3; Sequence=VSP_018720;
CC Note=Produced by alternative initiation at Met-41 of isoform A;
CC Name=C;
CC IsoId=Q04637-4; Sequence=VSP_018721;
CC Note=Produced by alternative initiation at Met-88 of isoform A;
CC Name=D;
CC IsoId=Q04637-5; Sequence=VSP_018722;
CC Note=Produced by alternative initiation at Met-165 of isoform A;
CC Name=E;
CC IsoId=Q04637-6; Sequence=VSP_018723;
CC Note=Produced by alternative initiation at Met-197 of isoform A;
CC Name=7;
CC IsoId=Q04637-7; Sequence=VSP_018723, VSP_047397;
CC Note=Produced by alternative splicing;
CC Name=8;
CC IsoId=Q04637-8; Sequence=VSP_047397;
CC Note=Produced by alternative splicing;
CC Name=9;
CC IsoId=Q04637-9; Sequence=VSP_047396;
CC Note=Produced by alternative splicing. Gene prediction based on
CC EST data;
CC -!- PTM: Phosphorylated at multiple sites in vivo. Phosphorylation at
CC Ser-1185 by PRKCA induces binding to MKNK1.
CC -!- PTM: Following infection by certain enteroviruses, rhinoviruses
CC and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or
CC the leader protease in the case of aphthoviruses. This shuts down
CC the capped cellular mRNA transcription.
CC -!- DISEASE: Parkinson disease 18 (PARK18) [MIM:614251]: An autosomal
CC dominant, late-onset form of Parkinson disease. Parkinson disease
CC is a complex neurodegenerative disorder characterized by
CC bradykinesia, resting tremor, muscular rigidity and postural
CC instability, as well as by a clinically significant response to
CC treatment with levodopa. The pathology involves the loss of
CC dopaminergic neurons in the substantia nigra and the presence of
CC Lewy bodies (intraneuronal accumulations of aggregated proteins),
CC in surviving neurons in various areas of the brain. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4G family.
CC -!- SIMILARITY: Contains 1 MI domain.
CC -!- SIMILARITY: Contains 1 MIF4G domain.
CC -!- SIMILARITY: Contains 1 W2 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC78444.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAC82471.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAA02185.1; Type=Frameshift; Positions=Several;
CC Sequence=BAD18554.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing;
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DR EMBL; D12686; BAA02185.1; ALT_FRAME; mRNA.
DR EMBL; AY082886; AAL92872.1; -; mRNA.
DR EMBL; AF281070; AAM69365.1; -; mRNA.
DR EMBL; AK131407; BAD18554.1; ALT_SEQ; mRNA.
DR EMBL; BX647812; CAI46013.1; -; mRNA.
DR EMBL; AC078797; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78257.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78259.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78262.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78263.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78264.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78265.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78266.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78267.1; -; Genomic_DNA.
DR EMBL; AF002816; AAC78443.1; -; mRNA.
DR EMBL; AF004836; AAC78444.1; ALT_INIT; Genomic_DNA.
DR EMBL; AF104913; AAC82471.1; ALT_INIT; mRNA.
DR EMBL; AJ001046; CAA04500.1; -; mRNA.
DR PIR; A44453; A44453.
DR RefSeq; NP_004944.3; NM_004953.4.
DR RefSeq; NP_886553.3; NM_182917.4.
DR RefSeq; NP_937884.1; NM_198241.2.
DR RefSeq; NP_937885.1; NM_198242.2.
DR RefSeq; XP_005247244.1; XM_005247187.1.
DR RefSeq; XP_005247245.1; XM_005247188.1.
DR RefSeq; XP_005247249.1; XM_005247192.1.
DR RefSeq; XP_005247253.1; XM_005247196.1.
DR RefSeq; XP_005247254.1; XM_005247197.1.
DR UniGene; Hs.433750; -.
DR PDB; 1LJ2; X-ray; 2.38 A; C/D=172-199.
DR PDB; 1UG3; X-ray; 2.24 A; A/B=1234-1571.
DR PDB; 2W97; X-ray; 2.29 A; E/F=609-622.
DR PDB; 4F02; X-ray; 2.00 A; C/F=178-203.
DR PDBsum; 1LJ2; -.
DR PDBsum; 1UG3; -.
DR PDBsum; 2W97; -.
DR PDBsum; 4F02; -.
DR DisProt; DP00406; -.
DR ProteinModelPortal; Q04637; -.
DR SMR; Q04637; 173-199, 751-991, 1234-1592.
DR DIP; DIP-1161N; -.
DR IntAct; Q04637; 30.
DR MINT; MINT-135718; -.
DR STRING; 9606.ENSP00000316879; -.
DR BindingDB; Q04637; -.
DR PhosphoSite; Q04637; -.
DR DMDM; 294862538; -.
DR PaxDb; Q04637; -.
DR PRIDE; Q04637; -.
DR DNASU; 1981; -.
DR Ensembl; ENST00000319274; ENSP00000323737; ENSG00000114867.
DR Ensembl; ENST00000342981; ENSP00000343450; ENSG00000114867.
DR Ensembl; ENST00000346169; ENSP00000316879; ENSG00000114867.
DR Ensembl; ENST00000350481; ENSP00000317600; ENSG00000114867.
DR Ensembl; ENST00000352767; ENSP00000338020; ENSG00000114867.
DR Ensembl; ENST00000382330; ENSP00000371767; ENSG00000114867.
DR Ensembl; ENST00000392537; ENSP00000376320; ENSG00000114867.
DR Ensembl; ENST00000414031; ENSP00000391935; ENSG00000114867.
DR Ensembl; ENST00000424196; ENSP00000416255; ENSG00000114867.
DR Ensembl; ENST00000434061; ENSP00000411826; ENSG00000114867.
DR Ensembl; ENST00000435046; ENSP00000404754; ENSG00000114867.
DR GeneID; 1981; -.
DR KEGG; hsa:1981; -.
DR UCSC; uc003fnv.4; human.
DR CTD; 1981; -.
DR GeneCards; GC03P184032; -.
DR HGNC; HGNC:3296; EIF4G1.
DR HPA; CAB014774; -.
DR HPA; HPA028487; -.
DR MIM; 600495; gene.
DR MIM; 614251; phenotype.
DR neXtProt; NX_Q04637; -.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA27722; -.
DR eggNOG; NOG301289; -.
DR HOVERGEN; HBG052083; -.
DR KO; K03260; -.
DR OMA; GSNWVPR; -.
DR OrthoDB; EOG7D59N2; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; EIF4G1; human.
DR EvolutionaryTrace; Q04637; -.
DR GeneWiki; Eukaryotic_translation_initiation_factor_4_gamma; -.
DR GenomeRNAi; 1981; -.
DR NextBio; 35489794; -.
DR PMAP-CutDB; Q04637; -.
DR PRO; PR:Q04637; -.
DR ArrayExpress; Q04637; -.
DR Bgee; Q04637; -.
DR CleanEx; HS_EIF4G1; -.
DR Genevestigator; Q04637; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; TAS:ProtInc.
DR GO; GO:0003743; F:translation initiation factor activity; TAS:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0000184; P:nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; TAS:Reactome.
DR GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; TAS:Reactome.
DR GO; GO:0006446; P:regulation of translational initiation; IMP:UniProtKB.
DR Gene3D; 1.25.40.180; -; 3.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003891; Initiation_fac_eIF4g_MI.
DR InterPro; IPR016021; MIF4-like_typ_1/2/3.
DR InterPro; IPR003890; MIF4G-like_typ-3.
DR InterPro; IPR003307; W2_domain.
DR Pfam; PF02847; MA3; 1.
DR Pfam; PF02854; MIF4G; 1.
DR Pfam; PF02020; W2; 1.
DR SMART; SM00515; eIF5C; 1.
DR SMART; SM00544; MA3; 1.
DR SMART; SM00543; MIF4G; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR PROSITE; PS51366; MI; 1.
DR PROSITE; PS51363; W2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Host-virus interaction; Initiation factor; Neurodegeneration;
KW Parkinson disease; Parkinsonism; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT CHAIN 1 1599 Eukaryotic translation initiation factor
FT 4 gamma 1.
FT /FTId=PRO_0000007786.
FT DOMAIN 565 792 MIF4G.
FT DOMAIN 1241 1363 MI.
FT DOMAIN 1433 1599 W2.
FT REGION 172 200 PABPC1-binding.
FT REGION 607 618 EIF4E-binding.
FT REGION 682 1085 eIF3/EIF4A-binding.
FT REGION 1450 1599 EIF4A-binding.
FT REGION 1585 1599 Necessary but not sufficient for MKNK1-
FT binding.
FT COMPBIAS 454 467 Poly-Glu.
FT COMPBIAS 501 504 Poly-Ala.
FT SITE 674 675 Cleavage; by foot-and-mouth disease virus
FT leader protease.
FT SITE 681 682 Cleavage; by enterovirus/rhinovirus
FT protease 2A.
FT MOD_RES 207 207 Phosphothreonine.
FT MOD_RES 223 223 Phosphothreonine.
FT MOD_RES 647 647 Phosphothreonine.
FT MOD_RES 1028 1028 Phosphoserine.
FT MOD_RES 1092 1092 Phosphoserine.
FT MOD_RES 1095 1095 N6-acetyllysine.
FT MOD_RES 1145 1145 Phosphoserine.
FT MOD_RES 1147 1147 Phosphoserine.
FT MOD_RES 1185 1185 Phosphoserine; by PKC/PRKCA.
FT MOD_RES 1187 1187 Phosphoserine.
FT MOD_RES 1209 1209 Phosphoserine.
FT MOD_RES 1211 1211 Phosphothreonine.
FT MOD_RES 1231 1231 Phosphoserine.
FT MOD_RES 1596 1596 Phosphoserine.
FT VAR_SEQ 1 196 Missing (in isoform E and isoform 7).
FT /FTId=VSP_018723.
FT VAR_SEQ 1 164 Missing (in isoform D).
FT /FTId=VSP_018722.
FT VAR_SEQ 1 87 Missing (in isoform C).
FT /FTId=VSP_018721.
FT VAR_SEQ 1 40 Missing (in isoform B).
FT /FTId=VSP_018720.
FT VAR_SEQ 48 48 R -> RQGGFRSL (in isoform 9).
FT /FTId=VSP_047396.
FT VAR_SEQ 696 696 P -> PQ (in isoform 7 and isoform 8).
FT /FTId=VSP_047397.
FT VARIANT 71 71 P -> S (in dbSNP:rs113810947).
FT /FTId=VAR_066571.
FT VARIANT 161 161 T -> A (in dbSNP:rs13319149).
FT /FTId=VAR_061147.
FT VARIANT 311 311 Y -> C (in dbSNP:rs16858632).
FT /FTId=VAR_055704.
FT VARIANT 432 432 M -> V (in dbSNP:rs2178403).
FT /FTId=VAR_063040.
FT VARIANT 466 468 Missing.
FT /FTId=VAR_066572.
FT VARIANT 502 502 A -> V (in PARK18; dbSNP:rs111290936).
FT /FTId=VAR_066573.
FT VARIANT 686 686 G -> C (found in patients with Parkinson
FT disease; dbSNP:rs112019125).
FT /FTId=VAR_066574.
FT VARIANT 696 696 P -> L (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036117.
FT VARIANT 806 806 I -> V (in dbSNP:rs62287499).
FT /FTId=VAR_066575.
FT VARIANT 829 829 T -> S (in dbSNP:rs111500185).
FT /FTId=VAR_066576.
FT VARIANT 1164 1164 S -> R (found in a patient with Parkinson
FT disease; dbSNP:rs113169049).
FT /FTId=VAR_066577.
FT VARIANT 1197 1197 R -> W (found in a patient with Parkinson
FT disease; dbSNP:rs113388242).
FT /FTId=VAR_066578.
FT VARIANT 1205 1205 R -> H (in PARK18; dbSNP:rs112176450).
FT /FTId=VAR_066579.
FT VARIANT 1229 1229 P -> A (in dbSNP:rs35629949).
FT /FTId=VAR_061148.
FT VARIANT 1233 1233 L -> P (in dbSNP:rs2230570).
FT /FTId=VAR_055705.
FT VARIANT 1257 1257 N -> S (in dbSNP:rs73053766).
FT /FTId=VAR_066580.
FT MUTAGEN 174 178 KRERK->AAAAA: Loss of PABPC1 binding;
FT when associated with 184-AAAA-187.
FT MUTAGEN 180 180 I->A: Loss of PABPC1 binding.
FT MUTAGEN 182 182 I->A: Loss of PABPC1 binding.
FT MUTAGEN 184 187 DPNQ->AAAA: Loss of PABPC1 binding; when
FT associated with 174-AAAAA-178.
FT MUTAGEN 192 192 I->A: Loss of PABPC1 binding.
FT MUTAGEN 196 196 I->A: Loss of PABPC1 binding.
FT MUTAGEN 612 612 Y->A,F: Abolishes binding to EIF4E.
FT MUTAGEN 617 618 LL->AA: Abolishes binding to EIF4E.
FT MUTAGEN 682 682 G->A,V,W,R,E: Reduced cleavage by
FT protease 2A from human rhinovirus 2.
FT MUTAGEN 768 768 L->A: Abolishes binding to EIF4A; when
FT associated with A-770 and A-775.
FT MUTAGEN 771 771 L->A: Abolishes binding to EIF4A; when
FT associated with A-767 and A-775.
FT MUTAGEN 776 776 F->A: Abolishes binding to EIF4A; when
FT associated with A-767 and A-770.
FT MUTAGEN 842 843 LL->AA: Abolishes binding to EIF4A; when
FT associated with A-850 and K-851.
FT MUTAGEN 851 852 FE->AK: Abolishes binding to EIF4A; when
FT associated with A-841 and A-842.
FT MUTAGEN 896 896 L->A: Abolishes binding to EIF4A; when
FT associated with A-92 and A-95.
FT MUTAGEN 902 902 I->A: Abolishes binding to EIF4A; when
FT associated with A-895 and A-95.
FT MUTAGEN 905 905 L->A: Abolishes binding to EIF4A; when
FT associated with A-895 and A-92.
FT MUTAGEN 974 974 R->A: Abolishes binding to EIF4A; when
FT associated with A-976.
FT MUTAGEN 977 977 F->A: Abolishes binding to EIF4A; when
FT associated with A-973.
FT MUTAGEN 985 985 L->A: Slightly reduced binding to EIF4A;
FT when associated with A-989.
FT MUTAGEN 990 990 W->A: Slightly reduced binding to EIF4A;
FT when associated with A-984.
FT CONFLICT 30 30 P -> R (in Ref. 9; AAC78443).
FT CONFLICT 138 138 F -> L (in Ref. 5; AAL92872/AAM69365).
FT CONFLICT 149 149 Q -> R (in Ref. 5; AAL92872/AAM69365).
FT CONFLICT 214 214 G -> S (in Ref. 1; BAA02185).
FT CONFLICT 462 462 E -> D (in Ref. 1; BAA02185).
FT CONFLICT 468 468 A -> V (in Ref. 1; BAA02185).
FT CONFLICT 474 474 A -> G (in Ref. 1; BAA02185).
FT CONFLICT 479 479 G -> R (in Ref. 1; BAA02185).
FT CONFLICT 604 604 L -> P (in Ref. 1; BAA02185, 5; AAL92872/
FT AAM69365 and 10; AAC82471).
FT CONFLICT 625 626 AS -> CQ (in Ref. 1; BAA02185).
FT CONFLICT 693 693 P -> A (in Ref. 1; BAA02185).
FT CONFLICT 696 696 P -> A (in Ref. 1; BAA02185).
FT CONFLICT 764 764 V -> W (in Ref. 1; BAA02185).
FT CONFLICT 878 878 G -> E (in Ref. 1; BAA02185).
FT CONFLICT 894 894 R -> C (in Ref. 1; BAA02185).
FT CONFLICT 1104 1104 K -> Q (in Ref. 1; BAA02185).
FT CONFLICT 1121 1121 N -> I (in Ref. 1; BAA02185).
FT CONFLICT 1185 1185 S -> T (in Ref. 1; BAA02185).
FT CONFLICT 1384 1384 C -> Y (in Ref. 6; CAI46013).
FT CONFLICT 1472 1472 Missing (in Ref. 1; BAA02185).
FT STRAND 181 183
FT HELIX 185 187
FT HELIX 193 197
FT HELIX 614 619
FT HELIX 1234 1256
FT HELIX 1259 1267
FT HELIX 1272 1274
FT HELIX 1275 1286
FT TURN 1287 1289
FT HELIX 1291 1306
FT HELIX 1312 1329
FT TURN 1330 1332
FT HELIX 1336 1344
FT HELIX 1345 1348
FT HELIX 1355 1362
FT TURN 1363 1365
FT HELIX 1366 1369
FT HELIX 1372 1387
FT HELIX 1389 1398
FT HELIX 1403 1405
FT HELIX 1413 1419
FT HELIX 1423 1425
FT HELIX 1439 1452
FT HELIX 1457 1467
FT HELIX 1470 1473
FT HELIX 1476 1489
FT STRAND 1494 1496
FT HELIX 1501 1514
FT HELIX 1518 1534
FT HELIX 1541 1551
FT HELIX 1557 1563
SQ SEQUENCE 1599 AA; 175491 MW; 324088B60863DA34 CRC64;
MNKAPQSTGP PPAPSPGLPQ PAFPPGQTAP VVFSTPQATQ MNTPSQPRQH FYPSRAQPPS
SAASRVQSAA PARPGPAAHV YPAGSQVMMI PSQISYPASQ GAYYIPGQGR STYVVPTQQY
PVQPGAPGFY PGASPTEFGT YAGAYYPAQG VQQFPTGVAP TPVLMNQPPQ IAPKRERKTI
RIRDPNQGGK DITEEIMSGA RTASTPTPPQ TGGGLEPQAN GETPQVAVIV RPDDRSQGAI
IADRPGLPGP EHSPSESQPS SPSPTPSPSP VLEPGSEPNL AVLSIPGDTM TTIQMSVEES
TPISRETGEP YRLSPEPTPL AEPILEVEVT LSKPVPESEF SSSPLQAPTP LASHTVEIHE
PNGMVPSEDL EPEVESSPEL APPPACPSES PVPIAPTAQP EELLNGAPSP PAVDLSPVSE
PEEQAKEVTA SMAPPTIPSA TPATAPSATS PAQEEEMEEE EEEEEGEAGE AGEAESEKGG
EELLPPESTP IPANLSQNLE AAAATQVAVS VPKRRRKIKE LNKKEAVGDL LDAFKEANPA
VPEVENQPPA GSNPGPESEG SGVPPRPEEA DETWDSKEDK IHNAENIQPG EQKYEYKSDQ
WKPLNLEEKK RYDREFLLGF QFIFASMQKP EGLPHISDVV LDKANKTPLR PLDPTRLQGI
NCGPDFTPSF ANLGRTTLST RGPPRGGPGG ELPRGPAGLG PRRSQQGPRK EPRKIIATVL
MTEDIKLNKA EKAWKPSSKR TAADKDRGEE DADGSKTQDL FRRVRSILNK LTPQMFQQLM
KQVTQLAIDT EERLKGVIDL IFEKAISEPN FSVAYANMCR CLMALKVPTT EKPTVTVNFR
KLLLNRCQKE FEKDKDDDEV FEKKQKEMDE AATAEERGRL KEELEEARDI ARRRSLGNIK
FIGELFKLKM LTEAIMHDCV VKLLKNHDEE SLECLCRLLT TIGKDLDFEK AKPRMDQYFN
QMEKIIKEKK TSSRIRFMLQ DVLDLRGSNW VPRRGDQGPK TIDQIHKEAE MEEHREHIKV
QQLMAKGSDK RRGGPPGPPI SRGLPLVDDG GWNTVPISKG SRPIDTSRLT KITKPGSIDS
NNQLFAPGGR LSWGKGSSGG SGAKPSDAAS EAARPATSTL NRFSALQQAV PTESTDNRRV
VQRSSLSRER GEKAGDRGDR LERSERGGDR GDRLDRARTP ATKRSFSKEV EERSRERPSQ
PEGLRKAASL TEDRDRGRDA VKREAALPPV SPLKAALSEE ELEKKSKAII EEYLHLNDMK
EAVQCVQELA SPSLLFIFVR HGVESTLERS AIAREHMGQL LHQLLCAGHL STAQYYQGLY
EILELAEDME IDIPHVWLYL AELVTPILQE GGVPMGELFR EITKPLRPLG KAASLLLEIL
GLLCKSMGPK KVGTLWREAG LSWKEFLPEG QDIGAFVAEQ KVEYTLGEES EAPGQRALPS
EELNRQLEKL LKEGSSNQRV FDWIEANLSE QQIVSNTLVR ALMTAVCYSA IIFETPLRVD
VAVLKARAKL LQKYLCDEQK ELQALYALQA LVVTLEQPPN LLRMFFDALY DEDVVKEDAF
YSWESSKDPA EQQGKGVALK SVTAFFKWLR EAEEESDHN
//
ID IF4G1_HUMAN Reviewed; 1599 AA.
AC Q04637; D3DNT2; D3DNT4; D3DNT5; E9PFM1; G5E9S1; O43177; O95066;
read moreAC Q5HYG0; Q6ZN21; Q8N102;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 4.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Eukaryotic translation initiation factor 4 gamma 1;
DE Short=eIF-4-gamma 1;
DE Short=eIF-4G 1;
DE Short=eIF-4G1;
DE AltName: Full=p220;
GN Name=EIF4G1; Synonyms=EIF4F, EIF4G, EIF4GI;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND VARIANT VAL-432.
RC TISSUE=Brain;
RX PubMed=1429670;
RA Yan R., Rychlik W., Etchison D., Rhoads R.E.;
RT "Amino acid sequence of the human protein synthesis initiation factor
RT eIF-4 gamma.";
RL J. Biol. Chem. 267:23226-23231(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND INTERACTION WITH PABPC1.
RX PubMed=9857202; DOI=10.1093/emboj/17.24.7480;
RA Imataka H., Gradi A., Sonenberg N.;
RT "A newly identified N-terminal amino acid sequence of human eIF4G
RT binds poly(A)-binding protein and functions in poly(A)-dependent
RT translation.";
RL EMBO J. 17:7480-7489(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM C).
RX PubMed=9418880;
RA Gradi A., Imataka H., Svitkin Y.V., Rom E., Raught B., Morino S.,
RA Sonenberg N.;
RT "A novel functional human eukaryotic translation initiation factor
RT 4G.";
RL Mol. Cell. Biol. 18:334-342(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 8), VARIANTS ALA-161 AND VAL-432,
RP AND ALTERNATIVE INITIATION.
RX PubMed=12052860; DOI=10.1128/MCB.22.13.4499-4511.2002;
RA Byrd M.P., Zamora M., Lloyd R.E.;
RT "Generation of multiple isoforms of eukaryotic translation initiation
RT factor 4GI by use of alternate translation initiation codons.";
RL Mol. Cell. Biol. 22:4499-4511(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A), AND VARIANT
RP ALA-161.
RC TISSUE=Endometrial tumor;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-206, NUCLEOTIDE SEQUENCE [GENOMIC
RP DNA] OF 180-234, VARIANT ALA-161, AND INTERACTION WITH ROTAVIRAL NSP3.
RX PubMed=9755181; DOI=10.1093/emboj/17.19.5811;
RA Piron M., Vende P., Cohen J., Poncet D.;
RT "Rotavirus RNA binding protein NSP3, interacts with eIF-4GI and evicts
RT the poly(A) binding protein from eIF4F.";
RL EMBO J. 17:5811-5821(1998).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 37-1599 (ISOFORM 8), INTERACTION WITH
RP EIF4A, VARIANTS ALA-161 AND VAL-432, AND MUTAGENESIS OF LEU-768;
RP LEU-771; PHE-776; 842-LEU-LEU-843; 851-PHE-GLU-852; LEU-896; ILE-902;
RP LEU-905; ARG-974; PHE-977; LEU-985 AND TRP-990.
RX PubMed=9372926;
RA Imataka H., Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) possesses
RT two separate and independent binding sites for eIF4A.";
RL Mol. Cell. Biol. 17:6940-6947(1997).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 605-721, INTERACTION WITH EIF4E, AND
RP MUTAGENESIS OF TYR-612 AND 617-LEU-LEU-618.
RX PubMed=7651417;
RA Mader S., Lee H., Pause A., Sonenberg N.;
RT "The translation initiation factor eIF-4E binds to a common motif
RT shared by the translation factor eIF-4 gamma and the translational
RT repressors 4E-binding proteins.";
RL Mol. Cell. Biol. 15:4990-4997(1995).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 682-912 (ISOFORM 8).
RA De Gregorio E.;
RL Submitted (AUG-1997) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP CLEAVAGE BY RHINOVIRUS AND COXSACKIEVIRUS PROTEASE.
RX PubMed=8396129;
RA Lamphear B.J., Yan R., Yang F., Waters D., Liebig H.-D., Klump H.,
RA Kuechler E., Skern T., Rhoads R.E.;
RT "Mapping the cleavage site in protein synthesis initiation factor eIF-
RT 4 gamma of the 2A proteases from human Coxsackievirus and
RT rhinovirus.";
RL J. Biol. Chem. 268:19200-19203(1993).
RN [14]
RP 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
RT of a regulator of 5'-cap function.";
RL Nature 371:762-767(1994).
RN [15]
RP INTERACTION WITH EIF4E AND EIF4EBP1.
RX PubMed=8521827;
RA Haghighat A., Mader S., Pause A., Sonenberg N.;
RT "Repression of cap-dependent translation by 4E-binding protein 1:
RT competition with p220 for binding to eukaryotic initiation factor-
RT 4E.";
RL EMBO J. 14:5701-5709(1995).
RN [16]
RP MUTAGENESIS OF GLY-682.
RX PubMed=8961935; DOI=10.1021/bi961864t;
RA Lamphear B.J., Rhoads R.E.;
RT "A single amino acid change in protein synthesis initiation factor 4G
RT renders cap-dependent translation resistant to picornaviral 2A
RT proteases.";
RL Biochemistry 35:15726-15733(1996).
RN [17]
RP CLEAVAGE BY POLIOVIRUS.
RX PubMed=9755863; DOI=10.1016/S0014-5793(98)01027-8;
RA Ventoso I., MacMillan S.E., Hershey J.W., Carrasco L.;
RT "Poliovirus 2A proteinase cleaves directly the eIF-4G subunit of eIF-
RT 4F complex.";
RL FEBS Lett. 435:79-83(1998).
RN [18]
RP REVIEW.
RX PubMed=10872469; DOI=10.1146/annurev.biochem.68.1.913;
RA Gingras A.-C., Raught B., Sonenberg N.;
RT "eIF4 initiation factors: effectors of mRNA recruitment to ribosomes
RT and regulators of translation.";
RL Annu. Rev. Biochem. 68:913-963(1999).
RN [19]
RP INTERACTION WITH MKNK1.
RX PubMed=9878069; DOI=10.1093/emboj/18.1.270;
RA Pyronnet S., Imataka H., Gingras A.-C., Fukunaga R., Hunter T.,
RA Sonenberg N.;
RT "Human eukaryotic translation initiation factor 4G (eIF4G) recruits
RT mnk1 to phosphorylate eIF4E.";
RL EMBO J. 18:270-279(1999).
RN [20]
RP INTERACTION WITH PABPC1, AND MUTAGENESIS OF 174-LYS--LYS-178 AND
RP 184-ASP--GLN-197.
RX PubMed=10996799; DOI=10.1016/S0960-9822(00)00701-6;
RA Wakiyama M., Imataka H., Sonenberg N.;
RT "Interaction of eIF4G with poly(A)-binding protein stimulates
RT translation and is critical for Xenopus oocyte maturation.";
RL Curr. Biol. 10:1147-1150(2000).
RN [21]
RP INTERACTION WITH PABPC1.
RX PubMed=10970864; DOI=10.1093/emboj/19.17.4723;
RA Gray N.K., Coller J.M., Dickson K.S., Wickens M.;
RT "Multiple portions of poly(A)-binding protein stimulate translation in
RT vivo.";
RL EMBO J. 19:4723-4733(2000).
RN [22]
RP CLEAVAGE BY FMDV AND HRV-2.
RX PubMed=11034318; DOI=10.1016/S0014-5793(00)01928-1;
RA Glaser W., Skern T.;
RT "Extremely efficient cleavage of eIF4G by picornaviral proteinases L
RT and 2A in vitro.";
RL FEBS Lett. 480:151-155(2000).
RN [23]
RP INTERACTION WITH MKNK2.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1231, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [26]
RP INTERACTION WITH CIRBP.
RX PubMed=16513844; DOI=10.1093/nar/gkj519;
RA Yang R., Weber D.J., Carrier F.;
RT "Post-transcriptional regulation of thioredoxin by the stress
RT inducible heterogeneous ribonucleoprotein A18.";
RL Nucleic Acids Res. 34:1224-1236(2006).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1092, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [28]
RP INTERACTION WITH RBM4.
RX PubMed=17284590; DOI=10.1073/pnas.0611015104;
RA Lin J.C., Hsu M., Tarn W.Y.;
RT "Cell stress modulates the function of splicing regulatory protein
RT RBM4 in translation control.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:2235-2240(2007).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [30]
RP INTERACTION WITH ROTAVIRUS A NSP3.
RX PubMed=18799579; DOI=10.1128/JVI.00872-08;
RA Harb M., Becker M.M., Vitour D., Baron C.H., Vende P., Brown S.C.,
RA Bolte S., Arold S.T., Poncet D.;
RT "Nuclear localization of cytoplasmic poly(A)-binding protein upon
RT rotavirus infection involves the interaction of NSP3 with eIF4G and
RT RoXaN.";
RL J. Virol. 82:11283-11293(2008).
RN [31]
RP INTERACTION WITH MIF4GD.
RX PubMed=18025107; DOI=10.1128/MCB.01500-07;
RA Cakmakci N.G., Lerner R.S., Wagner E.J., Zheng L., Marzluff W.F.;
RT "SLIP1, a factor required for activation of histone mRNA translation
RT by the stem-loop binding protein.";
RL Mol. Cell. Biol. 28:1182-1194(2008).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-207; THR-223; THR-647;
RP SER-1092 AND SER-1209, AND MASS SPECTROMETRY.
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 [33]
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.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [35]
RP IDENTIFICATION BY 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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-1095, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092;
RP SER-1185; SER-1187; SER-1209; THR-1211; SER-1231 AND SER-1596, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [39]
RP PHOSPHORYLATION AT SER-1185.
RX PubMed=21576361; DOI=10.1128/MCB.05589-11;
RA Dobrikov M., Dobrikova E., Shveygert M., Gromeier M.;
RT "Phosphorylation of eukaryotic translation initiation factor 4G1
RT (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to
RT Mnk1.";
RL Mol. Cell. Biol. 31:2947-2959(2011).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1028; SER-1092;
RP SER-1145; SER-1147; SER-1185; SER-1187; SER-1209; THR-1211; SER-1231
RP AND SER-1596, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.38 ANGSTROMS) OF 172-199 IN COMPLEX WITH
RP ROTAVIRAL NSP3, INTERACTION WITH PABPC1, AND MUTAGENESIS OF ILE-180;
RP ILE-182; ILE-192 AND ILE-196.
RX PubMed=12086624; DOI=10.1016/S1097-2765(02)00555-5;
RA Groft C.M., Burley S.K.;
RT "Recognition of eIF4G by rotavirus NSP3 reveals a basis for mRNA
RT circularization.";
RL Mol. Cell 9:1273-1283(2002).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (2.24 ANGSTROMS) OF 1234-1571.
RX PubMed=16698552; DOI=10.1016/j.str.2006.03.012;
RA Bellsolell L., Cho-Park P.F., Poulin F., Sonenberg N., Burley S.K.;
RT "Two structurally atypical HEAT domains in the C-terminal portion of
RT human eIF4G support binding to eIF4A and Mnk1.";
RL Structure 14:913-923(2006).
RN [44]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-696.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [45]
RP VARIANTS PARK18 VAL-502 AND HIS-1205, AND VARIANTS SER-71; ALA-161;
RP CYS-311; VAL-432; 466-GLY--ALA-468 DEL; CYS-686; VAL-806; SER-829;
RP ARG-1164; TRP-1197; ALA-1229; PRO-1233 AND SER-1257.
RX PubMed=21907011; DOI=10.1016/j.ajhg.2011.08.009;
RA Chartier-Harlin M.C., Dachsel J.C., Vilarino-Guell C., Lincoln S.J.,
RA Lepretre F., Hulihan M.M., Kachergus J., Milnerwood A.J., Tapia L.,
RA Song M.S., Le Rhun E., Mutez E., Larvor L., Duflot A.,
RA Vanbesien-Mailliot C., Kreisler A., Ross O.A., Nishioka K.,
RA Soto-Ortolaza A.I., Cobb S.A., Melrose H.L., Behrouz B., Keeling B.H.,
RA Bacon J.A., Hentati E., Williams L., Yanagiya A., Sonenberg N.,
RA Lockhart P.J., Zubair A.C., Uitti R.J., Aasly J.O., Krygowska-Wajs A.,
RA Opala G., Wszolek Z.K., Frigerio R., Maraganore D.M., Gosal D.,
RA Lynch T., Hutchinson M., Bentivoglio A.R., Valente E.M., Nichols W.C.,
RA Pankratz N., Foroud T., Gibson R.A., Hentati F., Dickson D.W.,
RA Destee A., Farrer M.J.;
RT "Translation initiator EIF4G1 mutations in familial Parkinson
RT disease.";
RL Am. J. Hum. Genet. 89:398-406(2011).
CC -!- FUNCTION: Component of the protein complex eIF4F, which is
CC involved in the recognition of the mRNA cap, ATP-dependent
CC unwinding of 5'-terminal secondary structure and recruitment of
CC mRNA to the ribosome.
CC -!- SUBUNIT: eIF4F is a multi-subunit complex, the composition of
CC which varies with external and internal environmental conditions.
CC It is composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3.
CC Interacts with eIF3, mutually exclusive with EIF4A1 or EIFA2,
CC EIF4E and through its N-terminus with PAPBC1. Interacts through
CC its C-terminus with the serine/threonine kinases MKNK1, and with
CC MKNK2. Appears to act as a scaffold protein, holding these enzymes
CC in place to phosphorylate EIF4E. Non-phosphorylated EIF4EBP1
CC competes with EIF4G1/EIF4G3 to interact with EIF4E; insulin
CC stimulated MAP-kinase (MAPK1 and MAPK3) phosphorylation of
CC EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3
CC to bind and consequent initiation of translation. EIF4G1/EIF4G3
CC interacts with PABPC1 to bring about circularization of the mRNA.
CC Rapamycin can attenuate insulin stimulation mediated by FKBPs.
CC Interacts with EIF4E3. Interacts with CIRBP and MIF4GD. Interacts
CC with rotavirus A NSP3; in this interaction, NSP3 takes the place
CC of PABPC1 thereby inducing shutoff of host protein synthesis.
CC Interacts with RBM4.
CC -!- INTERACTION:
CC O00571:DDX3X; NbExp=3; IntAct=EBI-73711, EBI-353779;
CC O75822:EIF3J; NbExp=2; IntAct=EBI-73711, EBI-366647;
CC P60842:EIF4A1; NbExp=7; IntAct=EBI-73711, EBI-73449;
CC P06730:EIF4E; NbExp=2; IntAct=EBI-73711, EBI-73440;
CC Q14103-4:HNRNPD; NbExp=3; IntAct=EBI-73711, EBI-432545;
CC P11940:PABPC1; NbExp=2; IntAct=EBI-73711, EBI-81531;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing, Alternative initiation; Named isoforms=8;
CC Name=A;
CC IsoId=Q04637-1; Sequence=Displayed;
CC Name=B;
CC IsoId=Q04637-3; Sequence=VSP_018720;
CC Note=Produced by alternative initiation at Met-41 of isoform A;
CC Name=C;
CC IsoId=Q04637-4; Sequence=VSP_018721;
CC Note=Produced by alternative initiation at Met-88 of isoform A;
CC Name=D;
CC IsoId=Q04637-5; Sequence=VSP_018722;
CC Note=Produced by alternative initiation at Met-165 of isoform A;
CC Name=E;
CC IsoId=Q04637-6; Sequence=VSP_018723;
CC Note=Produced by alternative initiation at Met-197 of isoform A;
CC Name=7;
CC IsoId=Q04637-7; Sequence=VSP_018723, VSP_047397;
CC Note=Produced by alternative splicing;
CC Name=8;
CC IsoId=Q04637-8; Sequence=VSP_047397;
CC Note=Produced by alternative splicing;
CC Name=9;
CC IsoId=Q04637-9; Sequence=VSP_047396;
CC Note=Produced by alternative splicing. Gene prediction based on
CC EST data;
CC -!- PTM: Phosphorylated at multiple sites in vivo. Phosphorylation at
CC Ser-1185 by PRKCA induces binding to MKNK1.
CC -!- PTM: Following infection by certain enteroviruses, rhinoviruses
CC and aphthoviruses, EIF4G1 is cleaved by the viral protease 2A, or
CC the leader protease in the case of aphthoviruses. This shuts down
CC the capped cellular mRNA transcription.
CC -!- DISEASE: Parkinson disease 18 (PARK18) [MIM:614251]: An autosomal
CC dominant, late-onset form of Parkinson disease. Parkinson disease
CC is a complex neurodegenerative disorder characterized by
CC bradykinesia, resting tremor, muscular rigidity and postural
CC instability, as well as by a clinically significant response to
CC treatment with levodopa. The pathology involves the loss of
CC dopaminergic neurons in the substantia nigra and the presence of
CC Lewy bodies (intraneuronal accumulations of aggregated proteins),
CC in surviving neurons in various areas of the brain. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic initiation factor 4G family.
CC -!- SIMILARITY: Contains 1 MI domain.
CC -!- SIMILARITY: Contains 1 MIF4G domain.
CC -!- SIMILARITY: Contains 1 W2 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC78444.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAC82471.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAA02185.1; Type=Frameshift; Positions=Several;
CC Sequence=BAD18554.1; Type=Miscellaneous discrepancy; Note=Aberrant splicing;
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DR EMBL; D12686; BAA02185.1; ALT_FRAME; mRNA.
DR EMBL; AY082886; AAL92872.1; -; mRNA.
DR EMBL; AF281070; AAM69365.1; -; mRNA.
DR EMBL; AK131407; BAD18554.1; ALT_SEQ; mRNA.
DR EMBL; BX647812; CAI46013.1; -; mRNA.
DR EMBL; AC078797; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW78257.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78259.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78262.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78263.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78264.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78265.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78266.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78267.1; -; Genomic_DNA.
DR EMBL; AF002816; AAC78443.1; -; mRNA.
DR EMBL; AF004836; AAC78444.1; ALT_INIT; Genomic_DNA.
DR EMBL; AF104913; AAC82471.1; ALT_INIT; mRNA.
DR EMBL; AJ001046; CAA04500.1; -; mRNA.
DR PIR; A44453; A44453.
DR RefSeq; NP_004944.3; NM_004953.4.
DR RefSeq; NP_886553.3; NM_182917.4.
DR RefSeq; NP_937884.1; NM_198241.2.
DR RefSeq; NP_937885.1; NM_198242.2.
DR RefSeq; XP_005247244.1; XM_005247187.1.
DR RefSeq; XP_005247245.1; XM_005247188.1.
DR RefSeq; XP_005247249.1; XM_005247192.1.
DR RefSeq; XP_005247253.1; XM_005247196.1.
DR RefSeq; XP_005247254.1; XM_005247197.1.
DR UniGene; Hs.433750; -.
DR PDB; 1LJ2; X-ray; 2.38 A; C/D=172-199.
DR PDB; 1UG3; X-ray; 2.24 A; A/B=1234-1571.
DR PDB; 2W97; X-ray; 2.29 A; E/F=609-622.
DR PDB; 4F02; X-ray; 2.00 A; C/F=178-203.
DR PDBsum; 1LJ2; -.
DR PDBsum; 1UG3; -.
DR PDBsum; 2W97; -.
DR PDBsum; 4F02; -.
DR DisProt; DP00406; -.
DR ProteinModelPortal; Q04637; -.
DR SMR; Q04637; 173-199, 751-991, 1234-1592.
DR DIP; DIP-1161N; -.
DR IntAct; Q04637; 30.
DR MINT; MINT-135718; -.
DR STRING; 9606.ENSP00000316879; -.
DR BindingDB; Q04637; -.
DR PhosphoSite; Q04637; -.
DR DMDM; 294862538; -.
DR PaxDb; Q04637; -.
DR PRIDE; Q04637; -.
DR DNASU; 1981; -.
DR Ensembl; ENST00000319274; ENSP00000323737; ENSG00000114867.
DR Ensembl; ENST00000342981; ENSP00000343450; ENSG00000114867.
DR Ensembl; ENST00000346169; ENSP00000316879; ENSG00000114867.
DR Ensembl; ENST00000350481; ENSP00000317600; ENSG00000114867.
DR Ensembl; ENST00000352767; ENSP00000338020; ENSG00000114867.
DR Ensembl; ENST00000382330; ENSP00000371767; ENSG00000114867.
DR Ensembl; ENST00000392537; ENSP00000376320; ENSG00000114867.
DR Ensembl; ENST00000414031; ENSP00000391935; ENSG00000114867.
DR Ensembl; ENST00000424196; ENSP00000416255; ENSG00000114867.
DR Ensembl; ENST00000434061; ENSP00000411826; ENSG00000114867.
DR Ensembl; ENST00000435046; ENSP00000404754; ENSG00000114867.
DR GeneID; 1981; -.
DR KEGG; hsa:1981; -.
DR UCSC; uc003fnv.4; human.
DR CTD; 1981; -.
DR GeneCards; GC03P184032; -.
DR HGNC; HGNC:3296; EIF4G1.
DR HPA; CAB014774; -.
DR HPA; HPA028487; -.
DR MIM; 600495; gene.
DR MIM; 614251; phenotype.
DR neXtProt; NX_Q04637; -.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA27722; -.
DR eggNOG; NOG301289; -.
DR HOVERGEN; HBG052083; -.
DR KO; K03260; -.
DR OMA; GSNWVPR; -.
DR OrthoDB; EOG7D59N2; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_1762; 3' -UTR-mediated translational regulation.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_6900; Immune System.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; EIF4G1; human.
DR EvolutionaryTrace; Q04637; -.
DR GeneWiki; Eukaryotic_translation_initiation_factor_4_gamma; -.
DR GenomeRNAi; 1981; -.
DR NextBio; 35489794; -.
DR PMAP-CutDB; Q04637; -.
DR PRO; PR:Q04637; -.
DR ArrayExpress; Q04637; -.
DR Bgee; Q04637; -.
DR CleanEx; HS_EIF4G1; -.
DR Genevestigator; Q04637; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016281; C:eukaryotic translation initiation factor 4F complex; TAS:ProtInc.
DR GO; GO:0003743; F:translation initiation factor activity; TAS:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0000184; P:nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; TAS:Reactome.
DR GO; GO:0000289; P:nuclear-transcribed mRNA poly(A) tail shortening; TAS:Reactome.
DR GO; GO:0006446; P:regulation of translational initiation; IMP:UniProtKB.
DR Gene3D; 1.25.40.180; -; 3.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003891; Initiation_fac_eIF4g_MI.
DR InterPro; IPR016021; MIF4-like_typ_1/2/3.
DR InterPro; IPR003890; MIF4G-like_typ-3.
DR InterPro; IPR003307; W2_domain.
DR Pfam; PF02847; MA3; 1.
DR Pfam; PF02854; MIF4G; 1.
DR Pfam; PF02020; W2; 1.
DR SMART; SM00515; eIF5C; 1.
DR SMART; SM00544; MA3; 1.
DR SMART; SM00543; MIF4G; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
DR PROSITE; PS51366; MI; 1.
DR PROSITE; PS51363; W2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative initiation;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Host-virus interaction; Initiation factor; Neurodegeneration;
KW Parkinson disease; Parkinsonism; Phosphoprotein; Polymorphism;
KW Protein biosynthesis; Reference proteome; RNA-binding;
KW Translation regulation.
FT CHAIN 1 1599 Eukaryotic translation initiation factor
FT 4 gamma 1.
FT /FTId=PRO_0000007786.
FT DOMAIN 565 792 MIF4G.
FT DOMAIN 1241 1363 MI.
FT DOMAIN 1433 1599 W2.
FT REGION 172 200 PABPC1-binding.
FT REGION 607 618 EIF4E-binding.
FT REGION 682 1085 eIF3/EIF4A-binding.
FT REGION 1450 1599 EIF4A-binding.
FT REGION 1585 1599 Necessary but not sufficient for MKNK1-
FT binding.
FT COMPBIAS 454 467 Poly-Glu.
FT COMPBIAS 501 504 Poly-Ala.
FT SITE 674 675 Cleavage; by foot-and-mouth disease virus
FT leader protease.
FT SITE 681 682 Cleavage; by enterovirus/rhinovirus
FT protease 2A.
FT MOD_RES 207 207 Phosphothreonine.
FT MOD_RES 223 223 Phosphothreonine.
FT MOD_RES 647 647 Phosphothreonine.
FT MOD_RES 1028 1028 Phosphoserine.
FT MOD_RES 1092 1092 Phosphoserine.
FT MOD_RES 1095 1095 N6-acetyllysine.
FT MOD_RES 1145 1145 Phosphoserine.
FT MOD_RES 1147 1147 Phosphoserine.
FT MOD_RES 1185 1185 Phosphoserine; by PKC/PRKCA.
FT MOD_RES 1187 1187 Phosphoserine.
FT MOD_RES 1209 1209 Phosphoserine.
FT MOD_RES 1211 1211 Phosphothreonine.
FT MOD_RES 1231 1231 Phosphoserine.
FT MOD_RES 1596 1596 Phosphoserine.
FT VAR_SEQ 1 196 Missing (in isoform E and isoform 7).
FT /FTId=VSP_018723.
FT VAR_SEQ 1 164 Missing (in isoform D).
FT /FTId=VSP_018722.
FT VAR_SEQ 1 87 Missing (in isoform C).
FT /FTId=VSP_018721.
FT VAR_SEQ 1 40 Missing (in isoform B).
FT /FTId=VSP_018720.
FT VAR_SEQ 48 48 R -> RQGGFRSL (in isoform 9).
FT /FTId=VSP_047396.
FT VAR_SEQ 696 696 P -> PQ (in isoform 7 and isoform 8).
FT /FTId=VSP_047397.
FT VARIANT 71 71 P -> S (in dbSNP:rs113810947).
FT /FTId=VAR_066571.
FT VARIANT 161 161 T -> A (in dbSNP:rs13319149).
FT /FTId=VAR_061147.
FT VARIANT 311 311 Y -> C (in dbSNP:rs16858632).
FT /FTId=VAR_055704.
FT VARIANT 432 432 M -> V (in dbSNP:rs2178403).
FT /FTId=VAR_063040.
FT VARIANT 466 468 Missing.
FT /FTId=VAR_066572.
FT VARIANT 502 502 A -> V (in PARK18; dbSNP:rs111290936).
FT /FTId=VAR_066573.
FT VARIANT 686 686 G -> C (found in patients with Parkinson
FT disease; dbSNP:rs112019125).
FT /FTId=VAR_066574.
FT VARIANT 696 696 P -> L (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036117.
FT VARIANT 806 806 I -> V (in dbSNP:rs62287499).
FT /FTId=VAR_066575.
FT VARIANT 829 829 T -> S (in dbSNP:rs111500185).
FT /FTId=VAR_066576.
FT VARIANT 1164 1164 S -> R (found in a patient with Parkinson
FT disease; dbSNP:rs113169049).
FT /FTId=VAR_066577.
FT VARIANT 1197 1197 R -> W (found in a patient with Parkinson
FT disease; dbSNP:rs113388242).
FT /FTId=VAR_066578.
FT VARIANT 1205 1205 R -> H (in PARK18; dbSNP:rs112176450).
FT /FTId=VAR_066579.
FT VARIANT 1229 1229 P -> A (in dbSNP:rs35629949).
FT /FTId=VAR_061148.
FT VARIANT 1233 1233 L -> P (in dbSNP:rs2230570).
FT /FTId=VAR_055705.
FT VARIANT 1257 1257 N -> S (in dbSNP:rs73053766).
FT /FTId=VAR_066580.
FT MUTAGEN 174 178 KRERK->AAAAA: Loss of PABPC1 binding;
FT when associated with 184-AAAA-187.
FT MUTAGEN 180 180 I->A: Loss of PABPC1 binding.
FT MUTAGEN 182 182 I->A: Loss of PABPC1 binding.
FT MUTAGEN 184 187 DPNQ->AAAA: Loss of PABPC1 binding; when
FT associated with 174-AAAAA-178.
FT MUTAGEN 192 192 I->A: Loss of PABPC1 binding.
FT MUTAGEN 196 196 I->A: Loss of PABPC1 binding.
FT MUTAGEN 612 612 Y->A,F: Abolishes binding to EIF4E.
FT MUTAGEN 617 618 LL->AA: Abolishes binding to EIF4E.
FT MUTAGEN 682 682 G->A,V,W,R,E: Reduced cleavage by
FT protease 2A from human rhinovirus 2.
FT MUTAGEN 768 768 L->A: Abolishes binding to EIF4A; when
FT associated with A-770 and A-775.
FT MUTAGEN 771 771 L->A: Abolishes binding to EIF4A; when
FT associated with A-767 and A-775.
FT MUTAGEN 776 776 F->A: Abolishes binding to EIF4A; when
FT associated with A-767 and A-770.
FT MUTAGEN 842 843 LL->AA: Abolishes binding to EIF4A; when
FT associated with A-850 and K-851.
FT MUTAGEN 851 852 FE->AK: Abolishes binding to EIF4A; when
FT associated with A-841 and A-842.
FT MUTAGEN 896 896 L->A: Abolishes binding to EIF4A; when
FT associated with A-92 and A-95.
FT MUTAGEN 902 902 I->A: Abolishes binding to EIF4A; when
FT associated with A-895 and A-95.
FT MUTAGEN 905 905 L->A: Abolishes binding to EIF4A; when
FT associated with A-895 and A-92.
FT MUTAGEN 974 974 R->A: Abolishes binding to EIF4A; when
FT associated with A-976.
FT MUTAGEN 977 977 F->A: Abolishes binding to EIF4A; when
FT associated with A-973.
FT MUTAGEN 985 985 L->A: Slightly reduced binding to EIF4A;
FT when associated with A-989.
FT MUTAGEN 990 990 W->A: Slightly reduced binding to EIF4A;
FT when associated with A-984.
FT CONFLICT 30 30 P -> R (in Ref. 9; AAC78443).
FT CONFLICT 138 138 F -> L (in Ref. 5; AAL92872/AAM69365).
FT CONFLICT 149 149 Q -> R (in Ref. 5; AAL92872/AAM69365).
FT CONFLICT 214 214 G -> S (in Ref. 1; BAA02185).
FT CONFLICT 462 462 E -> D (in Ref. 1; BAA02185).
FT CONFLICT 468 468 A -> V (in Ref. 1; BAA02185).
FT CONFLICT 474 474 A -> G (in Ref. 1; BAA02185).
FT CONFLICT 479 479 G -> R (in Ref. 1; BAA02185).
FT CONFLICT 604 604 L -> P (in Ref. 1; BAA02185, 5; AAL92872/
FT AAM69365 and 10; AAC82471).
FT CONFLICT 625 626 AS -> CQ (in Ref. 1; BAA02185).
FT CONFLICT 693 693 P -> A (in Ref. 1; BAA02185).
FT CONFLICT 696 696 P -> A (in Ref. 1; BAA02185).
FT CONFLICT 764 764 V -> W (in Ref. 1; BAA02185).
FT CONFLICT 878 878 G -> E (in Ref. 1; BAA02185).
FT CONFLICT 894 894 R -> C (in Ref. 1; BAA02185).
FT CONFLICT 1104 1104 K -> Q (in Ref. 1; BAA02185).
FT CONFLICT 1121 1121 N -> I (in Ref. 1; BAA02185).
FT CONFLICT 1185 1185 S -> T (in Ref. 1; BAA02185).
FT CONFLICT 1384 1384 C -> Y (in Ref. 6; CAI46013).
FT CONFLICT 1472 1472 Missing (in Ref. 1; BAA02185).
FT STRAND 181 183
FT HELIX 185 187
FT HELIX 193 197
FT HELIX 614 619
FT HELIX 1234 1256
FT HELIX 1259 1267
FT HELIX 1272 1274
FT HELIX 1275 1286
FT TURN 1287 1289
FT HELIX 1291 1306
FT HELIX 1312 1329
FT TURN 1330 1332
FT HELIX 1336 1344
FT HELIX 1345 1348
FT HELIX 1355 1362
FT TURN 1363 1365
FT HELIX 1366 1369
FT HELIX 1372 1387
FT HELIX 1389 1398
FT HELIX 1403 1405
FT HELIX 1413 1419
FT HELIX 1423 1425
FT HELIX 1439 1452
FT HELIX 1457 1467
FT HELIX 1470 1473
FT HELIX 1476 1489
FT STRAND 1494 1496
FT HELIX 1501 1514
FT HELIX 1518 1534
FT HELIX 1541 1551
FT HELIX 1557 1563
SQ SEQUENCE 1599 AA; 175491 MW; 324088B60863DA34 CRC64;
MNKAPQSTGP PPAPSPGLPQ PAFPPGQTAP VVFSTPQATQ MNTPSQPRQH FYPSRAQPPS
SAASRVQSAA PARPGPAAHV YPAGSQVMMI PSQISYPASQ GAYYIPGQGR STYVVPTQQY
PVQPGAPGFY PGASPTEFGT YAGAYYPAQG VQQFPTGVAP TPVLMNQPPQ IAPKRERKTI
RIRDPNQGGK DITEEIMSGA RTASTPTPPQ TGGGLEPQAN GETPQVAVIV RPDDRSQGAI
IADRPGLPGP EHSPSESQPS SPSPTPSPSP VLEPGSEPNL AVLSIPGDTM TTIQMSVEES
TPISRETGEP YRLSPEPTPL AEPILEVEVT LSKPVPESEF SSSPLQAPTP LASHTVEIHE
PNGMVPSEDL EPEVESSPEL APPPACPSES PVPIAPTAQP EELLNGAPSP PAVDLSPVSE
PEEQAKEVTA SMAPPTIPSA TPATAPSATS PAQEEEMEEE EEEEEGEAGE AGEAESEKGG
EELLPPESTP IPANLSQNLE AAAATQVAVS VPKRRRKIKE LNKKEAVGDL LDAFKEANPA
VPEVENQPPA GSNPGPESEG SGVPPRPEEA DETWDSKEDK IHNAENIQPG EQKYEYKSDQ
WKPLNLEEKK RYDREFLLGF QFIFASMQKP EGLPHISDVV LDKANKTPLR PLDPTRLQGI
NCGPDFTPSF ANLGRTTLST RGPPRGGPGG ELPRGPAGLG PRRSQQGPRK EPRKIIATVL
MTEDIKLNKA EKAWKPSSKR TAADKDRGEE DADGSKTQDL FRRVRSILNK LTPQMFQQLM
KQVTQLAIDT EERLKGVIDL IFEKAISEPN FSVAYANMCR CLMALKVPTT EKPTVTVNFR
KLLLNRCQKE FEKDKDDDEV FEKKQKEMDE AATAEERGRL KEELEEARDI ARRRSLGNIK
FIGELFKLKM LTEAIMHDCV VKLLKNHDEE SLECLCRLLT TIGKDLDFEK AKPRMDQYFN
QMEKIIKEKK TSSRIRFMLQ DVLDLRGSNW VPRRGDQGPK TIDQIHKEAE MEEHREHIKV
QQLMAKGSDK RRGGPPGPPI SRGLPLVDDG GWNTVPISKG SRPIDTSRLT KITKPGSIDS
NNQLFAPGGR LSWGKGSSGG SGAKPSDAAS EAARPATSTL NRFSALQQAV PTESTDNRRV
VQRSSLSRER GEKAGDRGDR LERSERGGDR GDRLDRARTP ATKRSFSKEV EERSRERPSQ
PEGLRKAASL TEDRDRGRDA VKREAALPPV SPLKAALSEE ELEKKSKAII EEYLHLNDMK
EAVQCVQELA SPSLLFIFVR HGVESTLERS AIAREHMGQL LHQLLCAGHL STAQYYQGLY
EILELAEDME IDIPHVWLYL AELVTPILQE GGVPMGELFR EITKPLRPLG KAASLLLEIL
GLLCKSMGPK KVGTLWREAG LSWKEFLPEG QDIGAFVAEQ KVEYTLGEES EAPGQRALPS
EELNRQLEKL LKEGSSNQRV FDWIEANLSE QQIVSNTLVR ALMTAVCYSA IIFETPLRVD
VAVLKARAKL LQKYLCDEQK ELQALYALQA LVVTLEQPPN LLRMFFDALY DEDVVKEDAF
YSWESSKDPA EQQGKGVALK SVTAFFKWLR EAEEESDHN
//
MIM
600495
*RECORD*
*FIELD* NO
600495
*FIELD* TI
*600495 EUKARYOTIC TRANSLATION INITIATION FACTOR 4-GAMMA, 1; EIF4G1
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 4G; EIF4G;;
read moreEIF4-GAMMA;;
EIF4GI
*FIELD* TX
DESCRIPTION
All eukaryotic cellular messenger RNAs are posttranscriptionally
modified by addition of an m(7)GTP moiety to the 5-prime terminus,
referred to as a cap. Recognition of the cap structure and unwinding of
mRNA secondary structure during the initiation phase of protein
synthesis is catalyzed by initiation factors of the eIF4 group. eIF4E
(133440) is a 25-kD cap-binding protein. eIF4A (see 602641) is a 46-kD
polypeptide that possesses ATP-dependent RNA helicase activity and
RNA-dependent ATPase activity. eIF4B (603928) is a 69-kD RNA-binding
protein that enhances the activity of eIF4A. eIF4-gamma, also known as
p220, is a 154-kD protein that forms various complexes with the other
eIF4 polypeptides. The complex of eIF4A, eIF4E, and eIF4-gamma has been
referred to as either eIF4F or eIF4. Collectively, these factors
facilitate the recruitment of mRNA to the ribosome, which is the
rate-limiting step for protein synthesis under normal conditions.
eIF4-gamma is the target for proteolytic cleavage during picornavirus
infection, an event that is thought to be responsible for the inhibition
of host cellular mRNA translation (Yan and Rhoads, 1995).
CLONING
By screening a rabbit brain library with oligonucleotide probes based on
the sequence of rabbit eIF4-gamma peptides, Yan et al. (1992) identified
partial eIF4-gamma cDNAs. They used the rabbit cDNAs as probes and
isolated human brain cDNAs encoding eIF4-gamma. The predicted human
protein contains 1,396 amino acids. Western blot analysis of
poliovirus-infected HeLa cell extracts revealed that eIF4-gamma has an
apparent molecular mass of 200 to 220 kD and is cleaved by this
picornavirus.
Imataka and Sonenberg (1997) stated that the N-terminal region of eIF4G
contains a binding site for eIF4E. They demonstrated that the central
third of eIF4G contains an eIF3 (see 602039)-binding region and an
eIF4A-binding domain. A second, separate eIF4A-binding site is present
in the C-terminal third. Neither eIF4A-binding domain alone activates
translation. In contrast to eIF4G, the eIF4G-related translation
regulator p97 (602325) binds eIF4A only through its N-terminal domain,
which is homologous to the central domain of eIF4G.
Gradi et al. (1998) identified a second human eIF4G gene. They
designated the original gene eIF4GI and the novel gene eIF4GII (EIF4G3;
603929).
Imataka et al. (1998) found that the human eIF4GI protein contains an
additional 156 N-terminal amino acids compared to the sequence published
by Yan et al. (1992). They demonstrated that this N-terminal region
binds poly(A)-binding protein (PABP; 604679).
GENE FUNCTION
Imataka et al. (1998) found that, in an in vitro translation system, an
N-terminal fragment of eIF4GI that included the PABP-binding site
inhibited poly(A)-dependent translation, but had no effect on
translation of a deadenylated mRNA. Imataka et al. (1998) concluded that
eIF4G probably functions in poly(A)-dependent translation in mammalian
cells.
Using coimmunoprecipitation experiments, Pyronnet et al. (1999)
demonstrated that MNK1 (MKNK1; 606724) is associated with the eIF4F
complex via an interaction with the C-terminal region of eIF4G. They
hypothesized that eIF4G provides a docking site for Mnk1 to
phosphorylate eIF4E.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich
elements in the 3-prime untranslated region. Rapid decay involves
AU-rich binding protein AUF1 (601324), which complexes with heat-shock
proteins HSC70 (600816) and HSP70 (see 140550), translation initiation
factor EIF4G, and PABP. AU-rich mRNA decay is associated with
displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation
of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation
of the ubiquitin-proteasome network, or inactivation of ubiquitinating
enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the
perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs
and AUF1 protein. These results link the rapid degradation of cytokine
mRNAs to the ubiquitin-proteasome pathway (Larola et al., 1999).
Amplification of cellular oncogenes is an important mechanism of altered
gene expression in human cancers. Using comparative genomic
hybridization, Brass et al. (1997) identified amplification at
3q26.1-q26.3 in 30% of squamous cell carcinomas of the lung. They then
combined an immunologic and molecular genetic approach to identify
amplified and tumor-relevant genes. They generated a cDNA expression
library from a tumor with the 3q amplification and hybridized the
expressed recombinant polypeptides with the autologous serum. In this
way they identified 17 antigens that induced an immune response in a
patient with squamous cell carcinoma. Four of the 17 cDNAs were nearly
identical with the eukaryotic translation initiation factor EIF4G. They
demonstrated that the EIF4G gene was amplified within 3q26-q27 in
independent squamous cell lung carcinomas.
E-cadherin (CDH1; 192090), an epithelial marker, is anchored at the
epithelial cell surface through interaction with p120 catenin (CTNND1;
601045). In inflammatory breast cancer, elevated cell surface expression
of E-cadherin causes tumor cells to cluster together in nonadherent
emboli rather than to adhere to stroma. Silvera et al. (2009) found that
EIF4G1 was overexpressed in a significant number of inflammatory breast
cancers. Silencing of EIF4G1 in SUM149 breast cancer cells via short
hairpin RNA reduced EIF4G1-dependent translation of p120 mRNA, resulting
in reduced cell surface E-cadherin expression and reduced tumorigenic
potential of SUM149 cells.
Thoreen et al. (2012) used high-resolution transcriptome-scale ribosome
profiling to monitor translation in mouse cells acutely treated with the
mTOR (601231) inhibitor Torin-1, which, unlike rapamycin, fully inhibits
mTOR complex 1 (mTORC1). Their data revealed a surprisingly simple model
of the mRNA features and mechanisms that confer mTORC1-dependent
translation control. The subset of mRNAs that are specifically regulated
by mTORC1 consists almost entirely of transcripts with established
5-prime terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1
(140572) and Ybx1 (154030), with previously unrecognized TOP or related
TOP-like motifs that were identified. Thoreen et al. (2012) found no
evidence to support proposals that mTORC1 preferentially regulates mRNAs
with increased 5-prime untranslated region length or complexity. mTORC1
phosphorylates a myriad of translational regulators, but how it controls
TOP mRNA translation is unknown. Remarkably, loss of just the 4EBP
family of translational repressors (see 602223), arguably the best
characterized mTORC1 substrates, is sufficient to render TOP and
TOP-like mRNA translation resistant to Torin-1. The E4BPs inhibit
translation initiation by interfering with the interaction between the
cap-binding protein eIF4E (133440) and eIF4G1. Loss of this interaction
diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much
more than other mRNAs, explaining why mTOR inhibition selectively
suppresses their translation.
BIOCHEMICAL FEATURES
Gross et al. (2003) reported the solution structure of the complex
between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids
393 to 490). Binding between these proteins triggered folding of the N
terminus of Eif4e with concomitant folding of Eif4g through a mutually
induced fit mechanism. Protein binding altered the conformation and/or
the stability of the cap binding slot, resulting in enhanced association
of Eif4e with the cap structure. Dissociation of the ternary complex was
slow, and the N terminus of Eif4e was required for these effects. Yeast
strains harboring mutants of Eif4e lacking key N-terminal residues
showed impaired growth, decreased polysome content, and reduced
interaction between Eif4e and Eif4g.
MAPPING
Using PCR analysis of human genomic DNA from human/hamster somatic cell
hybrids, Yan and Rhoads (1995) mapped the EIF4G gene to chromosome
3q27-qter. Brass et al. (1997) confirmed the localization of EIF4G to
3q27 by fluorescence in situ hybridization.
MOLECULAR GENETICS
In affected members of a large French family with late-onset Parkinson
disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011) identified a
heterozygous mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of
genomewide linkage analysis followed by direct sequencing. The EIF4G1
gene was subsequently sequenced in 95 probands with autosomal dominant
parkinsonism and 130 pathologically-defined cases of Lewy body disease,
which revealed 4 additional different missense mutations in 2 PD
patients and 2 Lewy body disease cases. These 4 variants were then
genotyped in a case-control series consisting of 4,483 individuals with
idiopathic PD and 3,865 controls: 3 additional patients carried only 2
of the variants, 2 with A502V (600495.0002) and 1 with a G686C
substitution. Coimmunoprecipitation studies indicated that the R1205H
and A502V substitutions impaired formation of the larger translation
initiation complex. The results were compatible with a dominant-negative
loss of function and age-dependent neurodegeneration. Hydroperoxide
treatment caused a profound loss of mitochondrial membrane potential in
cells expressing the mutations compared to cells with wildtype protein.
The findings implicated defects in mRNA translation initiation in
Parkinson disease. Chartier-Harlin et al. (2011) postulated that the
mutations hindered the ability of cells to respond rapidly and
dynamically to stress, presumably through changes in the translation of
existing mRNAs essential to cell survival.
*FIELD* AV
.0001
PARKINSON DISEASE 18
EIF4G1, ARG1205HIS
In 10 affected members of a large French family with late-onset
Parkinson disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011)
identified a heterozygous 3614G-A transition in exon 24 of the EIF4G1
gene, resulting in an arg1205-to-his (R1205H) substitution in a highly
conserved region. Among a cohort of 4,708 PD patients screened for
R1205H, 9 patients from 7 families from the US, Canada, Ireland, Italy,
and Tunisia were found to carry the mutation. Haplotype analysis
indicated a founder effect in these families and in the French family.
The mutation was not found in at least 4,050 controls.
Coimmunoprecipitation studies indicated that the A502V substitution
perturbs EIF4G1 binding to EIF3E (602210), which impairs formation of
the larger translation initiation complex. The results were compatible
with a dominant-negative loss of function and age-dependent
neurodegeneration. Hydroperoxide treatment caused a profound loss of
mitochondrial membrane potential in cells expressing the mutation
compared to cells with wildtype protein.
.0002
PARKINSON DISEASE 18
EIF4G1, ALA502VAL
In affected members of 4 unrelated families with Parkinson disease-18
(614251), Chartier-Harlin et al. (2011) identified a heterozygous
1505C-T transition in exon 10 of the EIF4G1 gene, resulting in an
ala502-to-val (A502V) substitution. The mutation was not found in over
3,865 controls and was conserved in most mammals, but was found in the
rabbit. Haplotype analysis suggested a founder effect.
Coimmunoprecipitation studies indicated that the A502V substitution
perturbs EIF4G1 binding to EIF4E (133440), which impairs formation of
the larger translation initiation complex. The results were compatible
with a dominant-negative loss of function and age-dependent
neurodegeneration. Hydroperoxide treatment caused a profound loss of
mitochondrial membrane potential in cells expressing the mutation
compared to cells with wildtype protein.
*FIELD* RF
1. Brass, N.; Heckel, D.; Sahin, U.; Pfreundschuh, M.; Sybrecht, G.
W.; Meese, E.: Translation initiation factor eIF-4gamma is encoded
by an amplified gene and induces an immune response in squamous cell
lung carcinoma. Hum. Molec. Genet. 6: 33-39, 1997.
2. Chartier-Harlin, M.-C.; Dachsel, J. C.; Vilarino-Guell, C.; Lincoln,
S. J.; Lepretre, F.; Hulihan, M. M.; Kachergus, J.; Milnerwood, A.
J.; Tapia, L.; Song, M. S.; Le Rhun, E.; Mutez, E.; and 38 others
: Translation initiator EIF4G1 mutations in familial Parkinson disease. Am.
J. Hum. Genet. 89: 398-406, 2011.
3. Gradi, A.; Imataka, H.; Svitkin, Y. V.; Rom, E.; Raught, B.; Morino,
S.; Sonenberg, N.: A novel functional human eukaryotic translation
initiation factor 4G. Molec. Cell. Biol. 18: 334-342, 1998.
4. Gross, J. D.; Moerke, N. J.; von der Haar, T.; Lugovskoy, A. A.;
Sachs, A. B.; McCarthy, J. E. G.; Wagner, G.: Ribosome loading onto
the mRNA cap is driven by conformational coupling between eIF4G and
eIF4E. Cell 115: 739-750, 2003.
5. Imataka, H.; Gradi, A.; Sonenberg, N.: A newly identified N-terminal
amino acid sequence of human eIF4G binds poly(A)-binding protein and
functions in poly(A)-dependent translation. EMBO J. 17: 7480-7489,
1998.
6. Imataka, H.; Sonenberg, N.: Human eukaryotic translation initiation
factor 4G (eIF4G) possesses two separate and independent binding sites
for eIF4A. Molec. Cell. Biol. 17: 6940-6947, 1997.
7. Larola, G.; Cuesta, R.; Brewer, G.; Schneider, R. J.: Control
of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284:
499-502, 1999.
8. Pyronnet, S.; Imataka, H.; Gingras, A.-C.; Fukunaga, R.; Hunter,
T.; Sonenberg, N.: Human eukaryotic translation initiation factor
4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279,
1999.
9. Silvera, D.; Arju, R.; Darvishian, F.; Levine, P. H.; Zolfaghari,
L.; Goldberg, J.; Hochman, T.; Formenti, S. C.; Schneider, R. J.:
Essential role for elF4GI overexpression in the pathogenesis of inflammatory
breast cancer. Nature Cell Biol. 11: 903-908, 2009.
10. Thoreen, C. C.; Chantranupong, L.; Keys, H. R.; Wang, T.; Gray,
N. S.; Sabatini, D. M.: A unifying model for mTORC1-mediated regulation
of mRNA translation. Nature 485: 109-113, 2012.
11. Yan, R.; Rhoads, R. E.: Human protein synthesis initiation factor
eIF-4-gamma is encoded by a single gene (EIF4G) that maps to chromosome
3q27-qter. Genomics 26: 394-398, 1995.
12. Yan, R.; Rychlik, W.; Etchison, D.; Rhoads, R. E.: Amino acid
sequence of the human protein synthesis initiation factor eIF-4-gamma. J.
Biol. Chem. 267: 23226-23231, 1992.
*FIELD* CN
Ada Hamosh - updated: 9/20/2012
Cassandra L. Kniffin - updated: 10/3/2011
Patricia A. Hartz - updated: 10/6/2010
Patricia A. Hartz - updated: 6/2/2006
Dawn Watkins-Chow - updated: 2/27/2002
Rebekah S. Rasooly - updated: 6/22/1999
Ada Hamosh - updated: 4/16/1999
Victor A. McKusick - updated: 2/12/1997
*FIELD* CD
Victor A. McKusick: 4/17/1995
*FIELD* ED
alopez: 09/24/2012
terry: 9/20/2012
carol: 10/3/2011
ckniffin: 10/3/2011
mgross: 10/8/2010
terry: 10/6/2010
carol: 8/20/2007
mgross: 6/8/2006
terry: 6/2/2006
mgross: 2/27/2002
mgross: 3/14/2000
alopez: 6/22/1999
alopez: 6/21/1999
alopez: 6/17/1999
alopez: 5/11/1999
alopez: 4/16/1999
terry: 2/12/1997
terry: 2/7/1997
terry: 4/18/1995
mark: 4/17/1995
*RECORD*
*FIELD* NO
600495
*FIELD* TI
*600495 EUKARYOTIC TRANSLATION INITIATION FACTOR 4-GAMMA, 1; EIF4G1
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 4G; EIF4G;;
read moreEIF4-GAMMA;;
EIF4GI
*FIELD* TX
DESCRIPTION
All eukaryotic cellular messenger RNAs are posttranscriptionally
modified by addition of an m(7)GTP moiety to the 5-prime terminus,
referred to as a cap. Recognition of the cap structure and unwinding of
mRNA secondary structure during the initiation phase of protein
synthesis is catalyzed by initiation factors of the eIF4 group. eIF4E
(133440) is a 25-kD cap-binding protein. eIF4A (see 602641) is a 46-kD
polypeptide that possesses ATP-dependent RNA helicase activity and
RNA-dependent ATPase activity. eIF4B (603928) is a 69-kD RNA-binding
protein that enhances the activity of eIF4A. eIF4-gamma, also known as
p220, is a 154-kD protein that forms various complexes with the other
eIF4 polypeptides. The complex of eIF4A, eIF4E, and eIF4-gamma has been
referred to as either eIF4F or eIF4. Collectively, these factors
facilitate the recruitment of mRNA to the ribosome, which is the
rate-limiting step for protein synthesis under normal conditions.
eIF4-gamma is the target for proteolytic cleavage during picornavirus
infection, an event that is thought to be responsible for the inhibition
of host cellular mRNA translation (Yan and Rhoads, 1995).
CLONING
By screening a rabbit brain library with oligonucleotide probes based on
the sequence of rabbit eIF4-gamma peptides, Yan et al. (1992) identified
partial eIF4-gamma cDNAs. They used the rabbit cDNAs as probes and
isolated human brain cDNAs encoding eIF4-gamma. The predicted human
protein contains 1,396 amino acids. Western blot analysis of
poliovirus-infected HeLa cell extracts revealed that eIF4-gamma has an
apparent molecular mass of 200 to 220 kD and is cleaved by this
picornavirus.
Imataka and Sonenberg (1997) stated that the N-terminal region of eIF4G
contains a binding site for eIF4E. They demonstrated that the central
third of eIF4G contains an eIF3 (see 602039)-binding region and an
eIF4A-binding domain. A second, separate eIF4A-binding site is present
in the C-terminal third. Neither eIF4A-binding domain alone activates
translation. In contrast to eIF4G, the eIF4G-related translation
regulator p97 (602325) binds eIF4A only through its N-terminal domain,
which is homologous to the central domain of eIF4G.
Gradi et al. (1998) identified a second human eIF4G gene. They
designated the original gene eIF4GI and the novel gene eIF4GII (EIF4G3;
603929).
Imataka et al. (1998) found that the human eIF4GI protein contains an
additional 156 N-terminal amino acids compared to the sequence published
by Yan et al. (1992). They demonstrated that this N-terminal region
binds poly(A)-binding protein (PABP; 604679).
GENE FUNCTION
Imataka et al. (1998) found that, in an in vitro translation system, an
N-terminal fragment of eIF4GI that included the PABP-binding site
inhibited poly(A)-dependent translation, but had no effect on
translation of a deadenylated mRNA. Imataka et al. (1998) concluded that
eIF4G probably functions in poly(A)-dependent translation in mammalian
cells.
Using coimmunoprecipitation experiments, Pyronnet et al. (1999)
demonstrated that MNK1 (MKNK1; 606724) is associated with the eIF4F
complex via an interaction with the C-terminal region of eIF4G. They
hypothesized that eIF4G provides a docking site for Mnk1 to
phosphorylate eIF4E.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich
elements in the 3-prime untranslated region. Rapid decay involves
AU-rich binding protein AUF1 (601324), which complexes with heat-shock
proteins HSC70 (600816) and HSP70 (see 140550), translation initiation
factor EIF4G, and PABP. AU-rich mRNA decay is associated with
displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation
of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation
of the ubiquitin-proteasome network, or inactivation of ubiquitinating
enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the
perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs
and AUF1 protein. These results link the rapid degradation of cytokine
mRNAs to the ubiquitin-proteasome pathway (Larola et al., 1999).
Amplification of cellular oncogenes is an important mechanism of altered
gene expression in human cancers. Using comparative genomic
hybridization, Brass et al. (1997) identified amplification at
3q26.1-q26.3 in 30% of squamous cell carcinomas of the lung. They then
combined an immunologic and molecular genetic approach to identify
amplified and tumor-relevant genes. They generated a cDNA expression
library from a tumor with the 3q amplification and hybridized the
expressed recombinant polypeptides with the autologous serum. In this
way they identified 17 antigens that induced an immune response in a
patient with squamous cell carcinoma. Four of the 17 cDNAs were nearly
identical with the eukaryotic translation initiation factor EIF4G. They
demonstrated that the EIF4G gene was amplified within 3q26-q27 in
independent squamous cell lung carcinomas.
E-cadherin (CDH1; 192090), an epithelial marker, is anchored at the
epithelial cell surface through interaction with p120 catenin (CTNND1;
601045). In inflammatory breast cancer, elevated cell surface expression
of E-cadherin causes tumor cells to cluster together in nonadherent
emboli rather than to adhere to stroma. Silvera et al. (2009) found that
EIF4G1 was overexpressed in a significant number of inflammatory breast
cancers. Silencing of EIF4G1 in SUM149 breast cancer cells via short
hairpin RNA reduced EIF4G1-dependent translation of p120 mRNA, resulting
in reduced cell surface E-cadherin expression and reduced tumorigenic
potential of SUM149 cells.
Thoreen et al. (2012) used high-resolution transcriptome-scale ribosome
profiling to monitor translation in mouse cells acutely treated with the
mTOR (601231) inhibitor Torin-1, which, unlike rapamycin, fully inhibits
mTOR complex 1 (mTORC1). Their data revealed a surprisingly simple model
of the mRNA features and mechanisms that confer mTORC1-dependent
translation control. The subset of mRNAs that are specifically regulated
by mTORC1 consists almost entirely of transcripts with established
5-prime terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1
(140572) and Ybx1 (154030), with previously unrecognized TOP or related
TOP-like motifs that were identified. Thoreen et al. (2012) found no
evidence to support proposals that mTORC1 preferentially regulates mRNAs
with increased 5-prime untranslated region length or complexity. mTORC1
phosphorylates a myriad of translational regulators, but how it controls
TOP mRNA translation is unknown. Remarkably, loss of just the 4EBP
family of translational repressors (see 602223), arguably the best
characterized mTORC1 substrates, is sufficient to render TOP and
TOP-like mRNA translation resistant to Torin-1. The E4BPs inhibit
translation initiation by interfering with the interaction between the
cap-binding protein eIF4E (133440) and eIF4G1. Loss of this interaction
diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much
more than other mRNAs, explaining why mTOR inhibition selectively
suppresses their translation.
BIOCHEMICAL FEATURES
Gross et al. (2003) reported the solution structure of the complex
between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids
393 to 490). Binding between these proteins triggered folding of the N
terminus of Eif4e with concomitant folding of Eif4g through a mutually
induced fit mechanism. Protein binding altered the conformation and/or
the stability of the cap binding slot, resulting in enhanced association
of Eif4e with the cap structure. Dissociation of the ternary complex was
slow, and the N terminus of Eif4e was required for these effects. Yeast
strains harboring mutants of Eif4e lacking key N-terminal residues
showed impaired growth, decreased polysome content, and reduced
interaction between Eif4e and Eif4g.
MAPPING
Using PCR analysis of human genomic DNA from human/hamster somatic cell
hybrids, Yan and Rhoads (1995) mapped the EIF4G gene to chromosome
3q27-qter. Brass et al. (1997) confirmed the localization of EIF4G to
3q27 by fluorescence in situ hybridization.
MOLECULAR GENETICS
In affected members of a large French family with late-onset Parkinson
disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011) identified a
heterozygous mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of
genomewide linkage analysis followed by direct sequencing. The EIF4G1
gene was subsequently sequenced in 95 probands with autosomal dominant
parkinsonism and 130 pathologically-defined cases of Lewy body disease,
which revealed 4 additional different missense mutations in 2 PD
patients and 2 Lewy body disease cases. These 4 variants were then
genotyped in a case-control series consisting of 4,483 individuals with
idiopathic PD and 3,865 controls: 3 additional patients carried only 2
of the variants, 2 with A502V (600495.0002) and 1 with a G686C
substitution. Coimmunoprecipitation studies indicated that the R1205H
and A502V substitutions impaired formation of the larger translation
initiation complex. The results were compatible with a dominant-negative
loss of function and age-dependent neurodegeneration. Hydroperoxide
treatment caused a profound loss of mitochondrial membrane potential in
cells expressing the mutations compared to cells with wildtype protein.
The findings implicated defects in mRNA translation initiation in
Parkinson disease. Chartier-Harlin et al. (2011) postulated that the
mutations hindered the ability of cells to respond rapidly and
dynamically to stress, presumably through changes in the translation of
existing mRNAs essential to cell survival.
*FIELD* AV
.0001
PARKINSON DISEASE 18
EIF4G1, ARG1205HIS
In 10 affected members of a large French family with late-onset
Parkinson disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011)
identified a heterozygous 3614G-A transition in exon 24 of the EIF4G1
gene, resulting in an arg1205-to-his (R1205H) substitution in a highly
conserved region. Among a cohort of 4,708 PD patients screened for
R1205H, 9 patients from 7 families from the US, Canada, Ireland, Italy,
and Tunisia were found to carry the mutation. Haplotype analysis
indicated a founder effect in these families and in the French family.
The mutation was not found in at least 4,050 controls.
Coimmunoprecipitation studies indicated that the A502V substitution
perturbs EIF4G1 binding to EIF3E (602210), which impairs formation of
the larger translation initiation complex. The results were compatible
with a dominant-negative loss of function and age-dependent
neurodegeneration. Hydroperoxide treatment caused a profound loss of
mitochondrial membrane potential in cells expressing the mutation
compared to cells with wildtype protein.
.0002
PARKINSON DISEASE 18
EIF4G1, ALA502VAL
In affected members of 4 unrelated families with Parkinson disease-18
(614251), Chartier-Harlin et al. (2011) identified a heterozygous
1505C-T transition in exon 10 of the EIF4G1 gene, resulting in an
ala502-to-val (A502V) substitution. The mutation was not found in over
3,865 controls and was conserved in most mammals, but was found in the
rabbit. Haplotype analysis suggested a founder effect.
Coimmunoprecipitation studies indicated that the A502V substitution
perturbs EIF4G1 binding to EIF4E (133440), which impairs formation of
the larger translation initiation complex. The results were compatible
with a dominant-negative loss of function and age-dependent
neurodegeneration. Hydroperoxide treatment caused a profound loss of
mitochondrial membrane potential in cells expressing the mutation
compared to cells with wildtype protein.
*FIELD* RF
1. Brass, N.; Heckel, D.; Sahin, U.; Pfreundschuh, M.; Sybrecht, G.
W.; Meese, E.: Translation initiation factor eIF-4gamma is encoded
by an amplified gene and induces an immune response in squamous cell
lung carcinoma. Hum. Molec. Genet. 6: 33-39, 1997.
2. Chartier-Harlin, M.-C.; Dachsel, J. C.; Vilarino-Guell, C.; Lincoln,
S. J.; Lepretre, F.; Hulihan, M. M.; Kachergus, J.; Milnerwood, A.
J.; Tapia, L.; Song, M. S.; Le Rhun, E.; Mutez, E.; and 38 others
: Translation initiator EIF4G1 mutations in familial Parkinson disease. Am.
J. Hum. Genet. 89: 398-406, 2011.
3. Gradi, A.; Imataka, H.; Svitkin, Y. V.; Rom, E.; Raught, B.; Morino,
S.; Sonenberg, N.: A novel functional human eukaryotic translation
initiation factor 4G. Molec. Cell. Biol. 18: 334-342, 1998.
4. Gross, J. D.; Moerke, N. J.; von der Haar, T.; Lugovskoy, A. A.;
Sachs, A. B.; McCarthy, J. E. G.; Wagner, G.: Ribosome loading onto
the mRNA cap is driven by conformational coupling between eIF4G and
eIF4E. Cell 115: 739-750, 2003.
5. Imataka, H.; Gradi, A.; Sonenberg, N.: A newly identified N-terminal
amino acid sequence of human eIF4G binds poly(A)-binding protein and
functions in poly(A)-dependent translation. EMBO J. 17: 7480-7489,
1998.
6. Imataka, H.; Sonenberg, N.: Human eukaryotic translation initiation
factor 4G (eIF4G) possesses two separate and independent binding sites
for eIF4A. Molec. Cell. Biol. 17: 6940-6947, 1997.
7. Larola, G.; Cuesta, R.; Brewer, G.; Schneider, R. J.: Control
of mRNA decay by heat shock-ubiquitin-proteasome pathway. Science 284:
499-502, 1999.
8. Pyronnet, S.; Imataka, H.; Gingras, A.-C.; Fukunaga, R.; Hunter,
T.; Sonenberg, N.: Human eukaryotic translation initiation factor
4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E. EMBO J. 18: 270-279,
1999.
9. Silvera, D.; Arju, R.; Darvishian, F.; Levine, P. H.; Zolfaghari,
L.; Goldberg, J.; Hochman, T.; Formenti, S. C.; Schneider, R. J.:
Essential role for elF4GI overexpression in the pathogenesis of inflammatory
breast cancer. Nature Cell Biol. 11: 903-908, 2009.
10. Thoreen, C. C.; Chantranupong, L.; Keys, H. R.; Wang, T.; Gray,
N. S.; Sabatini, D. M.: A unifying model for mTORC1-mediated regulation
of mRNA translation. Nature 485: 109-113, 2012.
11. Yan, R.; Rhoads, R. E.: Human protein synthesis initiation factor
eIF-4-gamma is encoded by a single gene (EIF4G) that maps to chromosome
3q27-qter. Genomics 26: 394-398, 1995.
12. Yan, R.; Rychlik, W.; Etchison, D.; Rhoads, R. E.: Amino acid
sequence of the human protein synthesis initiation factor eIF-4-gamma. J.
Biol. Chem. 267: 23226-23231, 1992.
*FIELD* CN
Ada Hamosh - updated: 9/20/2012
Cassandra L. Kniffin - updated: 10/3/2011
Patricia A. Hartz - updated: 10/6/2010
Patricia A. Hartz - updated: 6/2/2006
Dawn Watkins-Chow - updated: 2/27/2002
Rebekah S. Rasooly - updated: 6/22/1999
Ada Hamosh - updated: 4/16/1999
Victor A. McKusick - updated: 2/12/1997
*FIELD* CD
Victor A. McKusick: 4/17/1995
*FIELD* ED
alopez: 09/24/2012
terry: 9/20/2012
carol: 10/3/2011
ckniffin: 10/3/2011
mgross: 10/8/2010
terry: 10/6/2010
carol: 8/20/2007
mgross: 6/8/2006
terry: 6/2/2006
mgross: 2/27/2002
mgross: 3/14/2000
alopez: 6/22/1999
alopez: 6/21/1999
alopez: 6/17/1999
alopez: 5/11/1999
alopez: 4/16/1999
terry: 2/12/1997
terry: 2/7/1997
terry: 4/18/1995
mark: 4/17/1995
MIM
614251
*RECORD*
*FIELD* NO
614251
*FIELD* TI
#614251 PARKINSON DISEASE 18; PARK18
*FIELD* TX
A number sign (#) is used with this entry because Parkinson disease-18
read more(PARK18) is caused by heterozygous mutation in the EIF4G1 gene (600495)
on chromosome 3q27.
DESCRIPTION
Parkinson disease-18 is an autosomal dominant, adult-onset form of the
disorder. It is phenotypically similar to idiopathic Parkinson disease
(summary by Chartier-Harlin et al., 2011).
For a general phenotypic description and a discussion of genetic
heterogeneity of Parkinson disease (PD), see 168600.
CLINICAL FEATURES
Chartier-Harlin et al. (2011) reported a large French family with
classic late-onset Parkinson disease. The mean age at disease onset was
64 years, but there was a broad range (50 to 80 years). Affected
individuals had insidious onset of asymmetric resting tremor or akinetic
rigidity, and the parkinsonism followed a relatively long, mild course,
with preserved cognition. Symptoms responded well to L-dopa treatment.
Dopaminergic imaging in symptomatic patients was abnormal and
asymmetric.
INHERITANCE
The transmission pattern in the family reported by Chartier-Harlin et
al. (2011) was consistent with autosomal dominant inheritance.
MOLECULAR GENETICS
In affected members of a large French family with late-onset Parkinson
disease, Chartier-Harlin et al. (2011) identified a heterozygous
mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of genomewide
linkage analysis followed by direct sequencing. The EIF4G1 gene was
subsequently sequenced in 95 probands with autosomal dominant
parkinsonism and 130 pathologically-defined cases of Lewy body disease,
which revealed 4 additional different missense mutations in 2 PD
patients and 2 Lewy body disease cases. These 4 variants were then
genotyped in a case-control series consisting of 4,483 individuals with
idiopathic PD and 3,865 controls: 3 additional patients carried only 2
of the variants, 2 with A502V (600495.0002) and 1 with a G686C
substitution. Coimmunoprecipitation studies indicated that the R1205H
and A502V substitutions impaired formation of the larger translation
initiation complex. The results were compatible with a dominant-negative
loss of function and age-dependent neurodegeneration. Hydroperoxide
treatment caused a profound loss of mitochondrial membrane potential in
cells expressing the mutations compared to cells with wildtype protein.
Chartier-Harlin et al. (2011) postulated that the mutations hindered the
ability of cells to respond rapidly and dynamically to stress,
presumably through changes in the translation of existing mRNAs
essential to cell survival. The findings implicated defects in mRNA
translation initiation in Parkinson disease.
NOMENCLATURE
Parkinson disease caused by mutation in the EIF4G1 gene on chromosome
3q27 is designated here as PARK18. Although PARK18 had been used in the
literature to refer to a possible locus on chromosome 6p21 (Hamza et
al., 2010), validation for this locus had not yet been achieved (Mata et
al., 2011).
*FIELD* RF
1. Chartier-Harlin, M.-C.; Dachsel, J. C.; Vilarino-Guell, C.; Lincoln,
S. J.; Lepretre, F.; Hulihan, M. M.; Kachergus, J.; Milnerwood, A.
J.; Tapia, L.; Song, M. S.; Le Rhun, E.; Mutez, E.; and 38 others
: Translation initiator EIF4G1 mutations in familial Parkinson disease. Am.
J. Hum. Genet. 89: 398-406, 2011.
2. Hamza, T. H.; Zabetian, C. P.; Tenesa, A.; Laederach, A.; Montimurro,
J.; Yearout, D.; Kay, D. M.; Doheny, K. F.; Paschall, J.; Pugh, E.;
Kusel, V. I.; Collura, R.; Roberts, J.; Griffith, A.; Samii, A.; Scott,
W. K.; Nutt, J.; Factor, S. A.; Payami, H.: Common genetic variation
in the HLA region is associated with late-onset sporadic Parkinson's
disease. Nature Genet. 42: 781-785, 2010.
3. Mata, I. F.; Yearout, D.; Alvarez, V.; Coto, E.; de Mena, L.; Ribacoba,
R.; Lorenzo-Betancor, O.; Samaranch, L.; Pastor, P.; Cervantes, S.;
Infante, J.; Garcia-Gorostiaga, I.; Sierra, M.; Combarros, O.; Snapinn,
K. W.; Edwards, K. L.; Zabetian, C. P.: Replication of MAPT and SNCA,
but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov.
Disord. 26: 819-823, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Resting tremor;
Bradykinesia;
Rigidity;
Lewy bodies
MISCELLANEOUS:
Late-adult onset (range 50 to 80 years);
Insidious onset;
Long duration;
Favorable response to L-dopa treatment
MOLECULAR BASIS:
Caused by mutation in the eukaryotic translation initiation factor
4-gamma, 1 gene (EIF4G1, 600495.0001)
*FIELD* CD
Cassandra L. Kniffin: 9/26/2011
*FIELD* ED
joanna: 10/03/2011
ckniffin: 10/3/2011
*FIELD* CD
Cassandra L. Kniffin: 9/26/2011
*FIELD* ED
carol: 10/03/2011
ckniffin: 10/3/2011
*RECORD*
*FIELD* NO
614251
*FIELD* TI
#614251 PARKINSON DISEASE 18; PARK18
*FIELD* TX
A number sign (#) is used with this entry because Parkinson disease-18
read more(PARK18) is caused by heterozygous mutation in the EIF4G1 gene (600495)
on chromosome 3q27.
DESCRIPTION
Parkinson disease-18 is an autosomal dominant, adult-onset form of the
disorder. It is phenotypically similar to idiopathic Parkinson disease
(summary by Chartier-Harlin et al., 2011).
For a general phenotypic description and a discussion of genetic
heterogeneity of Parkinson disease (PD), see 168600.
CLINICAL FEATURES
Chartier-Harlin et al. (2011) reported a large French family with
classic late-onset Parkinson disease. The mean age at disease onset was
64 years, but there was a broad range (50 to 80 years). Affected
individuals had insidious onset of asymmetric resting tremor or akinetic
rigidity, and the parkinsonism followed a relatively long, mild course,
with preserved cognition. Symptoms responded well to L-dopa treatment.
Dopaminergic imaging in symptomatic patients was abnormal and
asymmetric.
INHERITANCE
The transmission pattern in the family reported by Chartier-Harlin et
al. (2011) was consistent with autosomal dominant inheritance.
MOLECULAR GENETICS
In affected members of a large French family with late-onset Parkinson
disease, Chartier-Harlin et al. (2011) identified a heterozygous
mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of genomewide
linkage analysis followed by direct sequencing. The EIF4G1 gene was
subsequently sequenced in 95 probands with autosomal dominant
parkinsonism and 130 pathologically-defined cases of Lewy body disease,
which revealed 4 additional different missense mutations in 2 PD
patients and 2 Lewy body disease cases. These 4 variants were then
genotyped in a case-control series consisting of 4,483 individuals with
idiopathic PD and 3,865 controls: 3 additional patients carried only 2
of the variants, 2 with A502V (600495.0002) and 1 with a G686C
substitution. Coimmunoprecipitation studies indicated that the R1205H
and A502V substitutions impaired formation of the larger translation
initiation complex. The results were compatible with a dominant-negative
loss of function and age-dependent neurodegeneration. Hydroperoxide
treatment caused a profound loss of mitochondrial membrane potential in
cells expressing the mutations compared to cells with wildtype protein.
Chartier-Harlin et al. (2011) postulated that the mutations hindered the
ability of cells to respond rapidly and dynamically to stress,
presumably through changes in the translation of existing mRNAs
essential to cell survival. The findings implicated defects in mRNA
translation initiation in Parkinson disease.
NOMENCLATURE
Parkinson disease caused by mutation in the EIF4G1 gene on chromosome
3q27 is designated here as PARK18. Although PARK18 had been used in the
literature to refer to a possible locus on chromosome 6p21 (Hamza et
al., 2010), validation for this locus had not yet been achieved (Mata et
al., 2011).
*FIELD* RF
1. Chartier-Harlin, M.-C.; Dachsel, J. C.; Vilarino-Guell, C.; Lincoln,
S. J.; Lepretre, F.; Hulihan, M. M.; Kachergus, J.; Milnerwood, A.
J.; Tapia, L.; Song, M. S.; Le Rhun, E.; Mutez, E.; and 38 others
: Translation initiator EIF4G1 mutations in familial Parkinson disease. Am.
J. Hum. Genet. 89: 398-406, 2011.
2. Hamza, T. H.; Zabetian, C. P.; Tenesa, A.; Laederach, A.; Montimurro,
J.; Yearout, D.; Kay, D. M.; Doheny, K. F.; Paschall, J.; Pugh, E.;
Kusel, V. I.; Collura, R.; Roberts, J.; Griffith, A.; Samii, A.; Scott,
W. K.; Nutt, J.; Factor, S. A.; Payami, H.: Common genetic variation
in the HLA region is associated with late-onset sporadic Parkinson's
disease. Nature Genet. 42: 781-785, 2010.
3. Mata, I. F.; Yearout, D.; Alvarez, V.; Coto, E.; de Mena, L.; Ribacoba,
R.; Lorenzo-Betancor, O.; Samaranch, L.; Pastor, P.; Cervantes, S.;
Infante, J.; Garcia-Gorostiaga, I.; Sierra, M.; Combarros, O.; Snapinn,
K. W.; Edwards, K. L.; Zabetian, C. P.: Replication of MAPT and SNCA,
but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov.
Disord. 26: 819-823, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Resting tremor;
Bradykinesia;
Rigidity;
Lewy bodies
MISCELLANEOUS:
Late-adult onset (range 50 to 80 years);
Insidious onset;
Long duration;
Favorable response to L-dopa treatment
MOLECULAR BASIS:
Caused by mutation in the eukaryotic translation initiation factor
4-gamma, 1 gene (EIF4G1, 600495.0001)
*FIELD* CD
Cassandra L. Kniffin: 9/26/2011
*FIELD* ED
joanna: 10/03/2011
ckniffin: 10/3/2011
*FIELD* CD
Cassandra L. Kniffin: 9/26/2011
*FIELD* ED
carol: 10/03/2011
ckniffin: 10/3/2011