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| - | ==STRUCTURE OF HUMAN EIF4E HOMOLOGOUS PROTEIN 4EHP WITH M7GTP== | + | |
| - | <StructureSection load='2jgb' size='340' side='right' caption='[[2jgb]], [[Resolution|resolution]] 1.70Å' scene=''> | + | ==Structure of human eIF4E homologous protein 4EHP with m7GTP== |
| | + | <StructureSection load='2jgb' size='340' side='right'caption='[[2jgb]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2jgb]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JGB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2JGB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2jgb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JGB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JGB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGT:7N-METHYL-8-HYDROGUANOSINE-5-TRIPHOSPHATE'>MGT</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2jgb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jgb OCA], [http://pdbe.org/2jgb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2jgb RCSB], [http://www.ebi.ac.uk/pdbsum/2jgb PDBsum]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MGT:7N-METHYL-8-HYDROGUANOSINE-5-TRIPHOSPHATE'>MGT</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2jgb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jgb OCA], [https://pdbe.org/2jgb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jgb RCSB], [https://www.ebi.ac.uk/pdbsum/2jgb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jgb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/4EBP1_HUMAN 4EBP1_HUMAN]] Regulates eIF4E activity by preventing its assembly into the eIF4F complex. Mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathways.<ref>PMID:7935836</ref> | + | [https://www.uniprot.org/uniprot/IF4E2_HUMAN IF4E2_HUMAN] Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation (PubMed:9582349, PubMed:17368478, PubMed:25624349). Acts as a repressor of translation initiation (PubMed:22751931). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity).[UniProtKB:Q8BMB3]<ref>PMID:17368478</ref> <ref>PMID:22751931</ref> <ref>PMID:25624349</ref> <ref>PMID:9582349</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jg/2jgb_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jg/2jgb_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2jgb ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | ==See Also== | | ==See Also== |
| - | *[[Eukaryotic initiation factor|Eukaryotic initiation factor]] | + | *[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cameron, A D]] | + | [[Category: Large Structures]] |
| - | [[Category: Knapp, S]] | + | [[Category: Cameron AD]] |
| - | [[Category: Rosettani, P]] | + | [[Category: Knapp S]] |
| - | [[Category: Rusconi, L]] | + | [[Category: Rosettani P]] |
| - | [[Category: Vismara, M G]] | + | [[Category: Rusconi L]] |
| - | [[Category: Cap-binding]]
| + | [[Category: Vismara MG]] |
| - | [[Category: Eif4e]]
| + | |
| - | [[Category: Eukaryotic initiation factor]]
| + | |
| - | [[Category: Initiation factor]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Protein biosynthesis]]
| + | |
| - | [[Category: Protein synthesis inhibitor]]
| + | |
| - | [[Category: Rna-binding]]
| + | |
| - | [[Category: Translation]]
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| - | [[Category: Translation regulation]]
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| Structural highlights
Function
IF4E2_HUMAN Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation (PubMed:9582349, PubMed:17368478, PubMed:25624349). Acts as a repressor of translation initiation (PubMed:22751931). In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap (By similarity).[UniProtKB:Q8BMB3][1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
All eukaryotic cellular mRNAs contain a 5' m(7)GpppN cap. In addition to conferring stability to the mRNA, the cap is required for pre-mRNA splicing, nuclear export and translation by providing an anchor point for protein binding. In translation, the interaction between the cap and the eukaryotic initiation factor 4E (eIF4E) is important in the recruitment of the mRNAs to the ribosome. Human 4EHP (h4EHP) is a homologue of eIF4E. Like eIF4E it is able to bind the cap but it appears to play a different cellular role, possibly being involved in the fine-tuning of protein expression levels. Here we use X-ray crystallography and isothermal titration calorimetry (ITC) to investigate further the binding of cap analogues and peptides to h4EHP. m(7)GTP binds to 4EHP 200-fold more weakly than it does to eIF4E with the guanine base sandwiched by a tyrosine and a tryptophan instead of two tryptophan residues as seen in eIF4E. The tyrosine resides on a loop that is longer in h4EHP than in eIF4E. The consequent conformational difference between the proteins allows the tyrosine to mimic the six-membered ring of the tryptophan in eIF4E and adopt an orientation that is similar to that seen for equivalent residues in other non-homologous cap-binding proteins. In the absence of ligand the binding site is incompletely formed with one of the aromatic residues being disordered and the side-chain of the other adopting a novel conformation. A peptide derived from the eIF4E inhibitory protein, 4E-BP1 binds h4EHP 100-fold less strongly than eIF4E but in a similar manner. Overall the data, combined with sequence analyses of 4EHP from evolutionary diverse species, strongly support the hypothesis that 4EHP plays a physiological role utilizing both cap-binding and protein-binding functions but which is distinct from eIF4E.
Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.,Rosettani P, Knapp S, Vismara MG, Rusconi L, Cameron AD J Mol Biol. 2007 May 4;368(3):691-705. Epub 2007 Feb 20. PMID:17368478[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Rosettani P, Knapp S, Vismara MG, Rusconi L, Cameron AD. Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms. J Mol Biol. 2007 May 4;368(3):691-705. Epub 2007 Feb 20. PMID:17368478 doi:10.1016/j.jmb.2007.02.019
- ↑ Morita M, Ler LW, Fabian MR, Siddiqui N, Mullin M, Henderson VC, Alain T, Fonseca BD, Karashchuk G, Bennett CF, Kabuta T, Higashi S, Larsson O, Topisirovic I, Smith RJ, Gingras AC, Sonenberg N. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol Cell Biol. 2012 Sep;32(17):3585-93. doi: 10.1128/MCB.00455-12. Epub 2012 Jul , 2. PMID:22751931 doi:http://dx.doi.org/10.1128/MCB.00455-12
- ↑ von Stechow L, Typas D, Carreras Puigvert J, Oort L, Siddappa R, Pines A, Vrieling H, van de Water B, Mullenders LH, Danen EH. The E3 ubiquitin ligase ARIH1 protects against genotoxic stress by initiating a 4EHP-mediated mRNA translation arrest. Mol Cell Biol. 2015 Apr;35(7):1254-68. doi: 10.1128/MCB.01152-14. Epub 2015 Jan, 26. PMID:25624349 doi:http://dx.doi.org/10.1128/MCB.01152-14
- ↑ Rom E, Kim HC, Gingras AC, Marcotrigiano J, Favre D, Olsen H, Burley SK, Sonenberg N. Cloning and characterization of 4EHP, a novel mammalian eIF4E-related cap-binding protein. J Biol Chem. 1998 May 22;273(21):13104-9. PMID:9582349
- ↑ Rosettani P, Knapp S, Vismara MG, Rusconi L, Cameron AD. Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms. J Mol Biol. 2007 May 4;368(3):691-705. Epub 2007 Feb 20. PMID:17368478 doi:10.1016/j.jmb.2007.02.019
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