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| | <StructureSection load='6d3k' size='340' side='right'caption='[[6d3k]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='6d3k' size='340' side='right'caption='[[6d3k]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6d3k]] is a 3 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=6D3K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D3K FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6d3k]] is a 3 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=6D3K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D3K FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EIF2AK2, PKR, PRKR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6d3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d3k OCA], [http://pdbe.org/6d3k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d3k RCSB], [http://www.ebi.ac.uk/pdbsum/6d3k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d3k 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=6d3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d3k OCA], [https://pdbe.org/6d3k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d3k RCSB], [https://www.ebi.ac.uk/pdbsum/6d3k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d3k ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/E2AK2_HUMAN E2AK2_HUMAN]] Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest.<ref>PMID:20395957</ref> | + | [https://www.uniprot.org/uniprot/E2AK2_HUMAN E2AK2_HUMAN] Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest.<ref>PMID:20395957</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cole, J L]] | + | [[Category: Cole JL]] |
| - | [[Category: Erlandsen, H]] | + | [[Category: Erlandsen H]] |
| - | [[Category: Mayo, C B]] | + | [[Category: Mayo CB]] |
| - | [[Category: Robinson, V L]] | + | [[Category: Robinson VL]] |
| - | [[Category: Activation loop swapping]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Dimer]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Unphosphorylated]]
| + | |
| Structural highlights
Function
E2AK2_HUMAN Following activation by double-stranded RNA in the presence of ATP, the kinase becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1, which leads to an inhibition of the initiation of protein synthesis. Double-stranded RNA is generated during the course of a viral infection. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity: phosphorylates CDK1 upon DNA damage. CDK1 phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest.[1]
Publication Abstract from PubMed
The RNA-activated protein kinase, PKR, is a key mediator of the innate immunity response to viral infection. Viral double-stranded RNAs induce PKR dimerization and autophosphorylation. The PKR kinase domain forms a back-to-back dimer. However, intermolecular ( trans) autophosphorylation is not feasible in this arrangement. We have obtained PKR kinase structures that resolves this dilemma. The kinase protomers interact via the known back-to-back interface as well as a front-to-front interface that is formed by exchange of activation segments. Mutational analysis of the front-to-front interface support a functional role in PKR activation. Molecular dynamics simulations reveal that the activation segment is highly dynamic in the front-to-front dimer and can adopt conformations conducive to phosphoryl transfer. We propose a mechanism where back-to-back dimerization induces a conformational change that activates PKR to phosphorylate a "substrate" kinase docked in a front-to-front geometry. This mechanism may be relevant to related kinases that phosphorylate the eukaryotic initiation factor eIF2alpha.
Structural Basis of Protein Kinase R Autophosphorylation.,Mayo CB, Erlandsen H, Mouser DJ, Feinstein AG, Robinson VL, May ER, Cole JL Biochemistry. 2019 Jul 9;58(27):2967-2977. doi: 10.1021/acs.biochem.9b00161. Epub, 2019 Jun 27. PMID:31246429[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yoon CH, Miah MA, Kim KP, Bae YS. New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses. EMBO Rep. 2010 May;11(5):393-9. doi: 10.1038/embor.2010.45. Epub 2010 Apr 16. PMID:20395957 doi:http://dx.doi.org/10.1038/embor.2010.45
- ↑ Mayo CB, Erlandsen H, Mouser DJ, Feinstein AG, Robinson VL, May ER, Cole JL. Structural Basis of Protein Kinase R Autophosphorylation. Biochemistry. 2019 Jul 9;58(27):2967-2977. doi: 10.1021/acs.biochem.9b00161. Epub, 2019 Jun 27. PMID:31246429 doi:http://dx.doi.org/10.1021/acs.biochem.9b00161
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