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| | ==eIF2B:eIF2 complex, phosphorylated on eIF2 alpha serine 52.== | | ==eIF2B:eIF2 complex, phosphorylated on eIF2 alpha serine 52.== |
| - | <StructureSection load='6i3m' size='340' side='right'caption='[[6i3m]], [[Resolution|resolution]] 3.93Å' scene=''> | + | <SX load='6i3m' size='340' side='right' viewer='molstar' caption='[[6i3m]], [[Resolution|resolution]] 3.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6i3m]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I3M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I3M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6i3m]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I3M FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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]] 3.93Å</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=6i3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i3m OCA], [http://pdbe.org/6i3m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i3m RCSB], [http://www.ebi.ac.uk/pdbsum/6i3m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i3m ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=6i3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i3m OCA], [https://pdbe.org/6i3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i3m RCSB], [https://www.ebi.ac.uk/pdbsum/6i3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i3m ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IF2A_YEAST IF2A_YEAST]] eIF-2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B. [[http://www.uniprot.org/uniprot/EI2BB_YEAST EI2BB_YEAST]] Acts as a regulatory component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. GCD6 and GCD7 repress GCN4 expression at the translational level by ensuring that ribosomes which have translated UORF1 will reinitiate at UORF2, -3, or -4 and thus fail to reach the GCN4 start site.<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> [[http://www.uniprot.org/uniprot/IF2B_YEAST IF2B_YEAST]] eIF-2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B. [[http://www.uniprot.org/uniprot/EI2BD_YEAST EI2BD_YEAST]] Acts as essential component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. GCD2 is also required for cell viability. Its function can partially be replaced by GCN3 under normal growth conditions in GCD2-defective mutants, under AA starvation conditions GCN3 is an antagonist (GCN4 translational activator).<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> [[http://www.uniprot.org/uniprot/IF2G_YEAST IF2G_YEAST]] eIF-2 functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B. [[http://www.uniprot.org/uniprot/EI2BA_YEAST EI2BA_YEAST]] Acts as a non-essential regulatory component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. Modulation of GCN3 regulatory function in response to amino acid availability occurs post-translationally.<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> [[http://www.uniprot.org/uniprot/EI2BE_YEAST EI2BE_YEAST]] Acts as a catalytic component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. GCD6 and GCD7 repress GCN4 expression at the translational level by ensuring that ribosomes which have translated UORF1 will reinitiate at UORF2, -3, or -4 and thus fail to reach the GCN4 start site.<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> [[http://www.uniprot.org/uniprot/EI2BG_YEAST EI2BG_YEAST]] Acts as essential component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. GCD1 stabilizes the interaction between eIF-2 and GCD6 and stimulates the catalytic activity in vitro.<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> | + | [https://www.uniprot.org/uniprot/EI2BA_YEAST EI2BA_YEAST] Acts as a non-essential regulatory component of the translation initiation factor 2B (eIF2-B or GCD complex), which catalyzes the exchange of eukaryotic initiation factor 2 (eIF-2)-bound GDP for GTP and is regulated by phosphorylated eIF-2. It activates the synthesis of GCN4 in yeast under amino acid starvation conditions by suppressing the inhibitory effects of multiple AUG codons present in the leader of GCN4 mRNA. It may promote either repression or activation of GCN4 expression depending on amino acid availability. Modulation of GCN3 regulatory function in response to amino acid availability occurs post-translationally.<ref>PMID:8506384</ref> <ref>PMID:9472020</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | Phosphorylation of eIF2alpha controls translation initiation by restricting the levels of active eIF2-GTP/Met-tRNAi ternary complexes (TC). This modulates the expression of all eukaryotic mRNAs and contributes to the cellular integrated stress response. Key to controlling the activity of eIF2 are translation factors eIF2B and eIF5, thought to primarily function with eIF2-GDP and TC respectively. Using a steady-state kinetics approach with purified proteins we demonstrate that eIF2B binds to eIF2 with equal affinity irrespective of the presence or absence of competing guanine nucleotides. We show that eIF2B can compete with Met-tRNAi for eIF2-GTP and can destabilize TC. When TC is formed with unphosphorylated eIF2, eIF5 can out-compete eIF2B to stabilize TC/eIF5 complexes. However when TC/eIF5 is formed with phosphorylated eIF2, eIF2B outcompetes eIF5 and destabilizes TC. These data uncover competition between eIF2B and eIF5 for TC and identify that phosphorylated eIF2-GTP translation initiation intermediate complexes can be inhibited by eIF2B.
| + | Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR). Phosphorylation of the translation initiation factor eIF2 alpha at a conserved serine residue mediates translational control at the ISR core. To provide insight into the mechanism of translational control we have determined the structures of eIF2 both in phosphorylated and unphosphorylated forms bound with its nucleotide exchange factor eIF2B by electron cryomicroscopy. The structures reveal that eIF2 undergoes large rearrangements to promote binding of eIF2alpha to the regulatory core of eIF2B comprised of the eIF2B alpha, beta and delta subunits. Only minor differences are observed between eIF2 and eIF2alphaP binding to eIF2B, suggesting that the higher affinity of eIF2alphaP for eIF2B drives translational control. We present a model for controlled nucleotide exchange and initiator tRNA binding to the eIF2/eIF2B complex. |
| | | | |
| - | Fail-safe control of translation initiation by dissociation of eIF2alpha phosphorylated ternary complexes.,Jennings MD, Kershaw CJ, Adomavicius T, Pavitt GD Elife. 2017 Mar 18;6. doi: 10.7554/eLife.24542. PMID:28315520<ref>PMID:28315520</ref>
| + | The structural basis of translational control by eIF2 phosphorylation.,Adomavicius T, Guaita M, Zhou Y, Jennings MD, Latif Z, Roseman AM, Pavitt GD Nat Commun. 2019 May 13;10(1):2136. doi: 10.1038/s41467-019-10167-3. PMID:31086188<ref>PMID:31086188</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> |
| | </div> | | </div> |
| | <div class="pdbe-citations 6i3m" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6i3m" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Adomavicius, T]] | + | [[Category: Saccharomyces cerevisiae S288C]] |
| - | [[Category: Pavitt, G D]] | + | [[Category: Adomavicius T]] |
| - | [[Category: Roseman, A M]] | + | [[Category: Pavitt GD]] |
| - | [[Category: Translation]] | + | [[Category: Roseman AM]] |
| - | [[Category: Translational control eif2 phosphorylation integrated stress response eif2b translation]]
| + | |
