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| | == Structural highlights == | | == Structural highlights == |
| | <table><tr><td colspan='2'>[[3j8b]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3j7j 3j7j]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3J8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3J8B FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3j8b]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3j7j 3j7j]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3J8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3J8B FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 9.3Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3j8c|3j8c]], [[4u1d|4u1d]], [[4u1c|4u1c]], [[4lct|4lct]], [[4b4t|4b4t]], [[4o8x|4o8x]], [[1rz4|1rz4]], [[3chm|3chm]], [[3j47|3j47]]</div></td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Ubiquitinyl_hydrolase_1 Ubiquitinyl hydrolase 1], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.19.12 3.4.19.12] </span></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=3j8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3j8b OCA], [https://pdbe.org/3j8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3j8b RCSB], [https://www.ebi.ac.uk/pdbsum/3j8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3j8b ProSAT]</span></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=3j8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3j8b OCA], [https://pdbe.org/3j8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3j8b RCSB], [https://www.ebi.ac.uk/pdbsum/3j8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3j8b ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/EIF3A_HUMAN EIF3A_HUMAN] RNA-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632, PubMed:11169732). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773, PubMed:27462815).[HAMAP-Rule:MF_03000]<ref>PMID:11169732</ref> <ref>PMID:17581632</ref> <ref>PMID:25849773</ref> <ref>PMID:27462815</ref> (Microbial infection) Essential for the initiation of translation on type-1 viral ribosomal entry sites (IRESs), like for HCV, PV, EV71 or BEV translation (PubMed:23766293, PubMed:24357634).<ref>PMID:23766293</ref> <ref>PMID:24357634</ref> (Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2 (PubMed:18056426).<ref>PMID:18056426</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Hepatitis C virus (HCV) and classical swine fever virus (CSFV) messenger RNAs contain related (HCV-like) internal ribosome entry sites (IRESs) that promote 5'-end independent initiation of translation, requiring only a subset of the eukaryotic initiation factors (eIFs) needed for canonical initiation on cellular mRNAs. Initiation on HCV-like IRESs relies on their specific interaction with the 40S subunit, which places the initiation codon into the P site, where it directly base-pairs with eIF2-bound initiator methionyl transfer RNA to form a 48S initiation complex. However, all HCV-like IRESs also specifically interact with eIF3 (refs 2, 5, 6, 7, 9, 10, 11, 12), but the role of this interaction in IRES-mediated initiation has remained unknown. During canonical initiation, eIF3 binds to the 40S subunit as a component of the 43S pre-initiation complex, and comparison of the ribosomal positions of eIF3 and the HCV IRES revealed that they overlap, so that their rearrangement would be required for formation of ribosomal complexes containing both components. Here we present a cryo-electron microscopy reconstruction of a 40S ribosomal complex containing eIF3 and the CSFV IRES. Remarkably, although the position and interactions of the CSFV IRES with the 40S subunit in this complex are similar to those of the HCV IRES in the 40S-IRES binary complex, eIF3 is completely displaced from its ribosomal position in the 43S complex, and instead interacts through its ribosome-binding surface exclusively with the apical region of domain III of the IRES. Our results suggest a role for the specific interaction of HCV-like IRESs with eIF3 in preventing ribosomal association of eIF3, which could serve two purposes: relieving the competition between the IRES and eIF3 for a common binding site on the 40S subunit, and reducing formation of 43S complexes, thereby favouring translation of viral mRNAs.
| + | Eukaryotic translation initiation requires the recruitment of the large, multiprotein eIF3 complex to the 40S ribosomal subunit. We present X-ray structures of all major components of the minimal, six-subunit Saccharomyces cerevisiae eIF3 core. These structures, together with electron microscopy reconstructions, cross-linking coupled to mass spectrometry, and integrative structure modeling, allowed us to position and orient all eIF3 components on the 40SeIF1 complex, revealing an extended, modular arrangement of eIF3 subunits. Yeast eIF3 engages 40S in a clamp-like manner, fully encircling 40S to position key initiation factors on opposite ends of the mRNA channel, providing a platform for the recruitment, assembly, and regulation of the translation initiation machinery. The structures of eIF3 components reported here also have implications for understanding the architecture of the mammalian 43S preinitiation complex and the complex of eIF3, 40S, and the hepatitis C internal ribosomal entry site RNA. |
| | | | |
| - | Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit.,Hashem Y, des Georges A, Dhote V, Langlois R, Liao HY, Grassucci RA, Pestova TV, Hellen CU, Frank J Nature. 2013 Nov 3. doi: 10.1038/nature12658. PMID:24185006<ref>PMID:24185006</ref>
| + | Molecular Architecture of the 40SeIF1eIF3 Translation Initiation Complex.,Erzberger JP, Stengel F, Pellarin R, Zhang S, Schaefer T, Aylett CH, Cimermancic P, Boehringer D, Sali A, Aebersold R, Ban N Cell. 2014 Aug 28;158(5):1123-35. doi: 10.1016/j.cell.2014.07.044. PMID:25171412<ref>PMID:25171412</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| Line 27: |
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| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ubiquitinyl hydrolase 1]]
| + | [[Category: Ban N]] |
| - | [[Category: Ban, N]] | + | [[Category: Erzberger JP]] |
| - | [[Category: Erzberger, J P]] | + | |
| - | [[Category: Translation]]
| + | |
| Structural highlights
Function
EIF3A_HUMAN RNA-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation (PubMed:17581632, PubMed:11169732). The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression (PubMed:25849773, PubMed:27462815).[HAMAP-Rule:MF_03000][1] [2] [3] [4] (Microbial infection) Essential for the initiation of translation on type-1 viral ribosomal entry sites (IRESs), like for HCV, PV, EV71 or BEV translation (PubMed:23766293, PubMed:24357634).[5] [6] (Microbial infection) In case of FCV infection, plays a role in the ribosomal termination-reinitiation event leading to the translation of VP2 (PubMed:18056426).[7]
Publication Abstract from PubMed
Eukaryotic translation initiation requires the recruitment of the large, multiprotein eIF3 complex to the 40S ribosomal subunit. We present X-ray structures of all major components of the minimal, six-subunit Saccharomyces cerevisiae eIF3 core. These structures, together with electron microscopy reconstructions, cross-linking coupled to mass spectrometry, and integrative structure modeling, allowed us to position and orient all eIF3 components on the 40SeIF1 complex, revealing an extended, modular arrangement of eIF3 subunits. Yeast eIF3 engages 40S in a clamp-like manner, fully encircling 40S to position key initiation factors on opposite ends of the mRNA channel, providing a platform for the recruitment, assembly, and regulation of the translation initiation machinery. The structures of eIF3 components reported here also have implications for understanding the architecture of the mammalian 43S preinitiation complex and the complex of eIF3, 40S, and the hepatitis C internal ribosomal entry site RNA.
Molecular Architecture of the 40SeIF1eIF3 Translation Initiation Complex.,Erzberger JP, Stengel F, Pellarin R, Zhang S, Schaefer T, Aylett CH, Cimermancic P, Boehringer D, Sali A, Aebersold R, Ban N Cell. 2014 Aug 28;158(5):1123-35. doi: 10.1016/j.cell.2014.07.044. PMID:25171412[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin L, Holbro T, Alonso G, Gerosa D, Burger MM. Molecular interaction between human tumor marker protein p150, the largest subunit of eIF3, and intermediate filament protein K7. J Cell Biochem. 2001;80(4):483-90. PMID:11169732 doi:<483::aid-jcb1002>3.0.co;2-b 10.1002/1097-4644(20010315)80:4<483::aid-jcb1002>3.0.co;2-b
- ↑ Masutani M, Sonenberg N, Yokoyama S, Imataka H. Reconstitution reveals the functional core of mammalian eIF3. EMBO J. 2007 Jul 25;26(14):3373-83. doi: 10.1038/sj.emboj.7601765. Epub 2007 Jun , 21. PMID:17581632 doi:http://dx.doi.org/10.1038/sj.emboj.7601765
- ↑ Lee AS, Kranzusch PJ, Cate JH. eIF3 targets cell-proliferation messenger RNAs for translational activation or repression. Nature. 2015 Jun 4;522(7554):111-4. doi: 10.1038/nature14267. Epub 2015 Apr 6. PMID:25849773 doi:http://dx.doi.org/10.1038/nature14267
- ↑ Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016 Aug 4;536(7614):96-9. PMID:27462815 doi:http://dx.doi.org/10.1038/nature18954
- ↑ Sun C, Querol-Audí J, Mortimer SA, Arias-Palomo E, Doudna JA, Nogales E, Cate JH. Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation. Nucleic Acids Res. 2013 Aug;41(15):7512-21. PMID:23766293 doi:10.1093/nar/gkt510
- ↑ Sweeney TR, Abaeva IS, Pestova TV, Hellen CU. The mechanism of translation initiation on Type 1 picornavirus IRESs. EMBO J. 2014 Jan 7;33(1):76-92. PMID:24357634 doi:10.1002/embj.201386124
- ↑ Poyry TA, Kaminski A, Connell EJ, Fraser CS, Jackson RJ. The mechanism of an exceptional case of reinitiation after translation of a long ORF reveals why such events do not generally occur in mammalian mRNA translation. Genes Dev. 2007 Dec 1;21(23):3149-62. doi: 10.1101/gad.439507. PMID:18056426 doi:http://dx.doi.org/10.1101/gad.439507
- ↑ Erzberger JP, Stengel F, Pellarin R, Zhang S, Schaefer T, Aylett CH, Cimermancic P, Boehringer D, Sali A, Aebersold R, Ban N. Molecular Architecture of the 40SeIF1eIF3 Translation Initiation Complex. Cell. 2014 Aug 28;158(5):1123-35. doi: 10.1016/j.cell.2014.07.044. PMID:25171412 doi:http://dx.doi.org/10.1016/j.cell.2014.07.044
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