|
|
| (13 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:2hw7.gif|left|200px]]<br /> | |
| - | <applet load="2hw7" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2hw7, resolution 2.71Å" /> | |
| - | '''Crystal Structure of Mnk2-D228G in complex with Staurosporine'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal Structure of Mnk2-D228G in complex with Staurosporine== |
| - | Autoinhibition is a recurring mode of protein kinase regulation and can be, based on diverse molecular mechanisms. Here, we show by crystal structure, analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity, studies and rational mutagenesis that nonphosphorylated mitogen-activated, protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by, conversion of the activation segment into an autoinhibitory module. In a, Mnk1 crystal structure, the activation segment is repositioned via a, Mnk-specific sequence insertion at the N-terminal lobe with the following, consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is, disrupted and (iv) the magnesium-binding loop is locked into an, ATP-competitive conformation. Consistently, deletion of the Mnk-specific, insertion or removal of a conserved phenylalanine side chain, which, induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1., Structural rearrangements required for the activation of Mnks are apparent, from the cocrystal structure of a Mnk2 D228G -staurosporine complex and, can be modeled on the basis of crystal packing interactions. Our data, suggest a novel regulatory mechanism specific for the Mnk subfamily. | + | <StructureSection load='2hw7' size='340' side='right'caption='[[2hw7]], [[Resolution|resolution]] 2.71Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2hw7]] is a 1 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=2HW7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HW7 FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.71Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STU:STAUROSPORINE'>STU</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2hw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hw7 OCA], [https://pdbe.org/2hw7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hw7 RCSB], [https://www.ebi.ac.uk/pdbsum/2hw7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hw7 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/MKNK2_HUMAN MKNK2_HUMAN] Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.<ref>PMID:11154262</ref> <ref>PMID:11463832</ref> <ref>PMID:12897141</ref> <ref>PMID:16111636</ref> <ref>PMID:17965020</ref> <ref>PMID:18299328</ref> <ref>PMID:20823271</ref> <ref>PMID:20927323</ref> <ref>PMID:21149447</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hw/2hw7_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </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/main_output.php?pdb_ID=2hw7 ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily. |
| | | | |
| - | ==About this Structure==
| + | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.,Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, Zweckstetter M, Jackle H, Wahl MC EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17. PMID:16917500<ref>PMID:16917500</ref> |
| - | 2HW7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN and STU as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2HW7 OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment., Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, Zweckstetter M, Jackle H, Wahl MC, EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16917500 16917500]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 2hw7" style="background-color:#fffaf0;"></div> |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Jauch, R.]]
| + | |
| - | [[Category: Wahl, M.C.]]
| + | |
| - | [[Category: STU]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: drug]]
| + | |
| - | [[Category: inhibitor]]
| + | |
| - | [[Category: phosphorylation]]
| + | |
| - | [[Category: protein kinases]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:37:27 2007''
| + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Jauch R]] |
| | + | [[Category: Wahl MC]] |
| Structural highlights
Function
MKNK2_HUMAN Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.[1] [2] [3] [4] [5] [6] [7] [8] [9]
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
Autoinhibition is a recurring mode of protein kinase regulation and can be based on diverse molecular mechanisms. Here, we show by crystal structure analysis, nuclear magnetic resonance (NMR)-based nucleotide affinity studies and rational mutagenesis that nonphosphorylated mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1 is autoinhibited by conversion of the activation segment into an autoinhibitory module. In a Mnk1 crystal structure, the activation segment is repositioned via a Mnk-specific sequence insertion at the N-terminal lobe with the following consequences: (i) the peptide substrate binding site is deconstructed, (ii) the interlobal cleft is narrowed, (iii) an essential Lys-Glu pair is disrupted and (iv) the magnesium-binding loop is locked into an ATP-competitive conformation. Consistently, deletion of the Mnk-specific insertion or removal of a conserved phenylalanine side chain, which induces a blockade of the ATP pocket, increase the ATP affinity of Mnk1. Structural rearrangements required for the activation of Mnks are apparent from the cocrystal structure of a Mnk2 D228G -staurosporine complex and can be modeled on the basis of crystal packing interactions. Our data suggest a novel regulatory mechanism specific for the Mnk subfamily.
Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment.,Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, Zweckstetter M, Jackle H, Wahl MC EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17. PMID:16917500[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
- ↑ Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol. 2001 Aug;21(16):5500-11. PMID:11463832 doi:http://dx.doi.org/10.1128/MCB.21.16.5500-5511.2001
- ↑ Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol Cell Biol. 2003 Aug;23(16):5692-705. PMID:12897141
- ↑ Buxade M, Parra JL, Rousseau S, Shpiro N, Marquez R, Morrice N, Bain J, Espel E, Proud CG. The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. Immunity. 2005 Aug;23(2):177-89. PMID:16111636 doi:http://dx.doi.org/10.1016/j.immuni.2005.06.009
- ↑ Buxade M, Morrice N, Krebs DL, Proud CG. The PSF.p54nrb complex is a novel Mnk substrate that binds the mRNA for tumor necrosis factor alpha. J Biol Chem. 2008 Jan 4;283(1):57-65. Epub 2007 Oct 26. PMID:17965020 doi:http://dx.doi.org/10.1074/jbc.M705286200
- ↑ Dolniak B, Katsoulidis E, Carayol N, Altman JK, Redig AJ, Tallman MS, Ueda T, Watanabe-Fukunaga R, Fukunaga R, Platanias LC. Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 , Feb 25. PMID:18299328 doi:http://dx.doi.org/10.1074/jbc.M708816200
- ↑ Shveygert M, Kaiser C, Bradrick SS, Gromeier M. Regulation of eukaryotic initiation factor 4E (eIF4E) phosphorylation by mitogen-activated protein kinase occurs through modulation of Mnk1-eIF4G interaction. Mol Cell Biol. 2010 Nov;30(21):5160-7. doi: 10.1128/MCB.00448-10. Epub 2010 Sep, 7. PMID:20823271 doi:http://dx.doi.org/10.1128/MCB.00448-10
- ↑ Li Y, Yue P, Deng X, Ueda T, Fukunaga R, Khuri FR, Sun SY. Protein phosphatase 2A negatively regulates eukaryotic initiation factor 4E phosphorylation and eIF4F assembly through direct dephosphorylation of Mnk and eIF4E. Neoplasia. 2010 Oct;12(10):848-55. PMID:20927323
- ↑ Joshi S, Sharma B, Kaur S, Majchrzak B, Ueda T, Fukunaga R, Verma AK, Fish EN, Platanias LC. Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis. J Biol Chem. 2011 Feb 25;286(8):6017-26. doi: 10.1074/jbc.M110.197921. Epub 2010 , Dec 13. PMID:21149447 doi:http://dx.doi.org/10.1074/jbc.M110.197921
- ↑ Jauch R, Cho MK, Jakel S, Netter C, Schreiter K, Aicher B, Zweckstetter M, Jackle H, Wahl MC. Mitogen-activated protein kinases interacting kinases are autoinhibited by a reprogrammed activation segment. EMBO J. 2006 Sep 6;25(17):4020-32. Epub 2006 Aug 17. PMID:16917500
|
