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| | ==Structure of 14-3-3 zeta in complex with CaMKK2 14-3-3 binding motif== | | ==Structure of 14-3-3 zeta in complex with CaMKK2 14-3-3 binding motif== |
| - | <StructureSection load='6eww' size='340' side='right' caption='[[6eww]], [[Resolution|resolution]] 2.68Å' scene=''> | + | <StructureSection load='6eww' size='340' side='right'caption='[[6eww]], [[Resolution|resolution]] 2.68Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6eww]] is a 8 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=6EWW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EWW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6eww]] is a 8 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=6EWW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EWW 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">X-ray diffraction, [[Resolution|Resolution]] 2.679Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">YWHAZ ([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=SEP:PHOSPHOSERINE'>SEP</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=6eww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eww OCA], [http://pdbe.org/6eww PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eww RCSB], [http://www.ebi.ac.uk/pdbsum/6eww PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eww 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=6eww FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eww OCA], [https://pdbe.org/6eww PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eww RCSB], [https://www.ebi.ac.uk/pdbsum/6eww PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eww ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/1433Z_HUMAN 1433Z_HUMAN]] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.<ref>PMID:9360956</ref> <ref>PMID:14578935</ref> <ref>PMID:15071501</ref> <ref>PMID:15644438</ref> <ref>PMID:16376338</ref> | + | [https://www.uniprot.org/uniprot/1433Z_HUMAN 1433Z_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.<ref>PMID:9360956</ref> <ref>PMID:14578935</ref> <ref>PMID:15071501</ref> <ref>PMID:15644438</ref> <ref>PMID:16376338</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca(2+)/calmodulin-dependent kinase (CaMK) family involved in adiposity regulation, glucose homeostasis and cancer. This upstream activator of CaMKI, CaMKIV and AMP-activated protein kinase is inhibited by phosphorylation, which also triggers an association with the scaffolding protein 14-3-3. However, the role of 14-3-3 in the regulation of CaMKK2 remains unknown. METHODS: The interaction between phosphorylated CaMKK2 and the 14-3-3gamma protein, as well as the architecture of their complex, were studied using enzyme activity measurements, small-angle x-ray scattering (SAXS), time-resolved fluorescence spectroscopy and protein crystallography. RESULTS: Our data suggest that the 14-3-3 protein binding does not inhibit the catalytic activity of phosphorylated CaMKK2 but rather slows down its dephosphorylation. Structural analysis indicated that the complex is flexible and that CaMKK2 is located outside the phosphopeptide-binding central channel of the 14-3-3gamma dimer. Furthermore, 14-3-3gamma appears to interact with and affect the structure of several regions of CaMKK2 outside the 14-3-3 binding motifs. In addition, the structural basis of interactions between 14-3-3 and the 14-3-3 binding motifs of CaMKK2 were elucidated by determining the crystal structures of phosphopeptides containing these motifs bound to 14-3-3. CONCLUSIONS: 14-3-3gamma protein directly interacts with the kinase domain of CaMKK2 and the region containing the inhibitory phosphorylation site Thr(145) within the N-terminal extension. GENERAL SIGNIFICANCE: Our results suggested that CaMKK isoforms differ in their 14-3-3-mediated regulations and that the interaction between 14-3-3 protein and the N-terminal 14-3-3-binding motif of CaMKK2 might be stabilized by small-molecule compounds. |
| | + | |
| | + | 14-3-3 protein directly interacts with the kinase domain of calcium/calmodulin-dependent protein kinase kinase (CaMKK2).,Psenakova K, Petrvalska O, Kylarova S, Lentini Santo D, Kalabova D, Herman P, Obsilova V, Obsil T Biochim Biophys Acta. 2018 Apr 10. pii: S0304-4165(18)30099-0. doi:, 10.1016/j.bbagen.2018.04.006. PMID:29649512<ref>PMID:29649512</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6eww" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Obsil, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Obsilova, V]]
| + | [[Category: Lentini Santo D]] |
| - | [[Category: Santo, D Lentini]] | + | [[Category: Obsil T]] |
| - | [[Category: 14-3-3 protein]] | + | [[Category: Obsilova V]] |
| - | [[Category: Calcium/calmodulin-dependent protein kinase kinase 2]] | + | |
| - | [[Category: Camkk2]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a member of the Ca(2+)/calmodulin-dependent kinase (CaMK) family involved in adiposity regulation, glucose homeostasis and cancer. This upstream activator of CaMKI, CaMKIV and AMP-activated protein kinase is inhibited by phosphorylation, which also triggers an association with the scaffolding protein 14-3-3. However, the role of 14-3-3 in the regulation of CaMKK2 remains unknown. METHODS: The interaction between phosphorylated CaMKK2 and the 14-3-3gamma protein, as well as the architecture of their complex, were studied using enzyme activity measurements, small-angle x-ray scattering (SAXS), time-resolved fluorescence spectroscopy and protein crystallography. RESULTS: Our data suggest that the 14-3-3 protein binding does not inhibit the catalytic activity of phosphorylated CaMKK2 but rather slows down its dephosphorylation. Structural analysis indicated that the complex is flexible and that CaMKK2 is located outside the phosphopeptide-binding central channel of the 14-3-3gamma dimer. Furthermore, 14-3-3gamma appears to interact with and affect the structure of several regions of CaMKK2 outside the 14-3-3 binding motifs. In addition, the structural basis of interactions between 14-3-3 and the 14-3-3 binding motifs of CaMKK2 were elucidated by determining the crystal structures of phosphopeptides containing these motifs bound to 14-3-3. CONCLUSIONS: 14-3-3gamma protein directly interacts with the kinase domain of CaMKK2 and the region containing the inhibitory phosphorylation site Thr(145) within the N-terminal extension. GENERAL SIGNIFICANCE: Our results suggested that CaMKK isoforms differ in their 14-3-3-mediated regulations and that the interaction between 14-3-3 protein and the N-terminal 14-3-3-binding motif of CaMKK2 might be stabilized by small-molecule compounds.
14-3-3 protein directly interacts with the kinase domain of calcium/calmodulin-dependent protein kinase kinase (CaMKK2).,Psenakova K, Petrvalska O, Kylarova S, Lentini Santo D, Kalabova D, Herman P, Obsilova V, Obsil T Biochim Biophys Acta. 2018 Apr 10. pii: S0304-4165(18)30099-0. doi:, 10.1016/j.bbagen.2018.04.006. PMID:29649512[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dubois T, Rommel C, Howell S, Steinhussen U, Soneji Y, Morrice N, Moelling K, Aitken A. 14-3-3 is phosphorylated by casein kinase I on residue 233. Phosphorylation at this site in vivo regulates Raf/14-3-3 interaction. J Biol Chem. 1997 Nov 14;272(46):28882-8. PMID:9360956
- ↑ Zheng W, Zhang Z, Ganguly S, Weller JL, Klein DC, Cole PA. Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation. Nat Struct Biol. 2003 Dec;10(12):1054-7. Epub 2003 Oct 26. PMID:14578935 doi:10.1038/nsb1005
- ↑ Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004 Apr 21;23(8):1889-99. Epub 2004 Apr 8. PMID:15071501 doi:10.1038/sj.emboj.7600194
- ↑ Ganguly S, Weller JL, Ho A, Chemineau P, Malpaux B, Klein DC. Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1222-7. Epub 2005 Jan 11. PMID:15644438 doi:0406871102
- ↑ Gu YM, Jin YH, Choi JK, Baek KH, Yeo CY, Lee KY. Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon. FEBS Lett. 2006 Jan 9;580(1):305-10. Epub 2005 Dec 19. PMID:16376338 doi:S0014-5793(05)01485-7
- ↑ Psenakova K, Petrvalska O, Kylarova S, Lentini Santo D, Kalabova D, Herman P, Obsilova V, Obsil T. 14-3-3 protein directly interacts with the kinase domain of calcium/calmodulin-dependent protein kinase kinase (CaMKK2). Biochim Biophys Acta. 2018 Apr 10. pii: S0304-4165(18)30099-0. doi:, 10.1016/j.bbagen.2018.04.006. PMID:29649512 doi:http://dx.doi.org/10.1016/j.bbagen.2018.04.006
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