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| | <StructureSection load='6una' size='340' side='right'caption='[[6una]], [[Resolution|resolution]] 2.55Å' scene=''> | | <StructureSection load='6una' size='340' side='right'caption='[[6una]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6una]] 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=6UNA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UNA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6una]] 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=6UNA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UNA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.554Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAPK12, ERK6, SAPK3 ([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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=6una FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6una OCA], [https://pdbe.org/6una PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6una RCSB], [https://www.ebi.ac.uk/pdbsum/6una PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6una ProSAT]</span></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=6una FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6una OCA], [http://pdbe.org/6una PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6una RCSB], [http://www.ebi.ac.uk/pdbsum/6una PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6una ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN]] Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. | + | [https://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN] Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.<ref>PMID:8633070</ref> <ref>PMID:9430721</ref> <ref>PMID:10848581</ref> <ref>PMID:14592936</ref> <ref>PMID:17724032</ref> <ref>PMID:20605917</ref> <ref>PMID:21172807</ref> | + | [https://www.uniprot.org/uniprot/MK12_HUMAN MK12_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.<ref>PMID:8633070</ref> <ref>PMID:9430721</ref> <ref>PMID:10848581</ref> <ref>PMID:14592936</ref> <ref>PMID:17724032</ref> <ref>PMID:20605917</ref> <ref>PMID:21172807</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6una" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6una" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Mitogen-activated protein kinase]]
| + | [[Category: Aoto PC]] |
| - | [[Category: Aoto, P C]] | + | [[Category: Dyson HJ]] |
| - | [[Category: Dyson, H J]] | + | [[Category: Stanfield RL]] |
| - | [[Category: Stanfield, R L]] | + | [[Category: Wilson IA]] |
| - | [[Category: Wilson, I A]] | + | [[Category: Wright PE]] |
| - | [[Category: Wright, P E]] | + | |
| - | [[Category: Inactive kinase]]
| + | |
| - | [[Category: Mapk]]
| + | |
| - | [[Category: Mapk12]]
| + | |
| - | [[Category: Mitogen activated protein kinase]]
| + | |
| - | [[Category: P38 gamma]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
MK12_HUMAN Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples.
Function
MK12_HUMAN Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The inactive state of mitogen-activated protein kinases (MAPKs) adopts an open conformation while the active state exists in a compact form stabilized by phosphorylation. In the active state, eukaryotic kinases undergo breathing motions related to substrate binding and product release that have not previously been detected in the inactive state. However, docking interactions of partner proteins with inactive MAPK kinases exhibit allostery in binding of activating kinases. Interactions at a site distant from the activation loop are coupled to the configuration of the activation loop, suggesting that the inactive state may also undergo concerted dynamics. X-ray crystallographic studies of nonphosphorylated, inactive p38gamma reveal differences in domain orientations and active site structure in the two molecules in the asymmetric unit. One molecule resembles an inactive kinase with an open active site. The second molecule has a rotation of the N-lobe that leads to partial compaction of the active site, resulting in a conformation that is intermediate between the inactive open state and the fully closed state of the activated kinase. Although the compact state of apo p38gamma displays several of the features of the activated enzyme, it remains catalytically inert. In solution, the kinase fluctuates on a millisecond time scale between the open ground state and a weakly populated excited state that is similar in structure to the compact state observed in the crystal. The nuclear magnetic resonance and crystal structure data imply that interconversion between the open and compact states involves a molecular switch associated with the DFG loop.
A Dynamic Switch in Inactive p38gamma Leads to an Excited State on the Pathway to an Active Kinase.,Aoto PC, Stanfield RL, Wilson IA, Dyson HJ, Wright PE Biochemistry. 2019 Dec 13. doi: 10.1021/acs.biochem.9b00932. PMID:31794659[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355-9. PMID:8633070
- ↑ Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998 Jan 16;273(3):1741-8. PMID:9430721
- ↑ Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000 Jul;20(13):4543-52. PMID:10848581
- ↑ Ho RC, Alcazar O, Fujii N, Hirshman MF, Goodyear LJ. p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2004 Feb;286(2):R342-9. Epub 2003 Oct 30. PMID:14592936 doi:10.1152/ajpregu.00563.2003
- ↑ Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G. p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408. Epub 2007 Aug 27. PMID:17724032 doi:10.1074/jbc.M703857200
- ↑ Sabio G, Cerezo-Guisado MI, Del Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JS, Campbell DG, Centeno F, Cuenda A. p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010 Aug 1;123(Pt 15):2596-604. doi: 10.1242/jcs.066514. Epub 2010, Jul 6. PMID:20605917 doi:10.1242/jcs.066514
- ↑ Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L, Kallio MJ. Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death. J Cell Sci. 2011 Jan 15;124(Pt 2):216-27. doi: 10.1242/jcs.068254. Epub 2010 Dec , 15. PMID:21172807 doi:10.1242/jcs.068254
- ↑ Aoto PC, Stanfield RL, Wilson IA, Dyson HJ, Wright PE. A Dynamic Switch in Inactive p38gamma Leads to an Excited State on the Pathway to an Active Kinase. Biochemistry. 2019 Dec 13. doi: 10.1021/acs.biochem.9b00932. PMID:31794659 doi:http://dx.doi.org/10.1021/acs.biochem.9b00932
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