View source for 9ocw


==A constitutively active construct of eukaryotic elongation factor 2 kinase==
<StructureSection load='9ocw' size='340' side='right'caption='[[9ocw]], [[Resolution|resolution]] 2.27&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ocw]] 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=9OCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9OCW 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]] 2.27&#8491;</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=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PHD:ASPARTYL+PHOSPHATE'>PHD</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=9ocw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ocw OCA], [https://pdbe.org/9ocw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ocw RCSB], [https://www.ebi.ac.uk/pdbsum/9ocw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ocw ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CALM1_HUMAN CALM1_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4.  The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14.
== Function ==
[https://www.uniprot.org/uniprot/EF2K_HUMAN EF2K_HUMAN] Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.<ref>PMID:14709557</ref> <ref>PMID:9144159</ref> [https://www.uniprot.org/uniprot/CALM1_HUMAN CALM1_HUMAN] Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).<ref>PMID:16760425</ref> <ref>PMID:23893133</ref> <ref>PMID:26969752</ref> <ref>PMID:27165696</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Eukaryotic elongation factor 2 kinase (eEF-2K), a member of the alpha-kinase family, modulates translational rates by phosphorylating eEF-2, a GTPase that facilitates the translocation of the nascent chain on the ribosome during the elongation phase of protein synthesis. eEF-2K is regulated by diverse cellular cues, many of which sensitize it to the Ca(2+)-effector protein calmodulin (CaM). CaM, which binds and allosterically activates eEF-2K in the presence of Ca(2+), contains two structural "lobes," each with a pair of Ca(2+)-binding EF hands. Using kinetic analysis, we demonstrate that the isolated C-terminal lobe of CaM (CaM(C)) is sufficient to engage and fully activate eEF-2K in a Ca(2+)-dependent fashion. Genetically fusing CaM(C) to the N terminus of eEF-2K, upstream of its critical CaM-targeting motif via a flexible 2-glycine linker, results in a chimeric species (CaM(C) is linked to N-truncated eEF-2K [C-LiNK]) that is constitutively active independent of external CaM and Ca(2+). A structure of the C-LiNK functional core reveals no substantial deviation in the overall conformations of the structural modules and orientations of key catalytic-site residues relative to the heterodimeric complex between full-length CaM and eEF-2K. These observations demonstrate that, in contrast to other CaM-regulated kinases, CaM(C) alone is sufficient to activate eEF-2K fully. The proximity effect of CaM(C) in the context of C-LiNK removes the requirement for external Ca(2+), whose apparent role is to enhance the CaM affinity of eEF-2K and drive kinase activation. Further, the responsiveness of eEF-2K to regulatory stimuli in cells appears to be lost in C-LiNK, presumably due to its permanently "on" state.

The critical role of the C-terminal lobe of calmodulin in activating eukaryotic elongation factor 2 kinase.,Long KJ, Browning LS, Piserchio A, Isiorho EA, Gadallah MI, Douangvilay J, Wang EY, Kalugin JK, Brodbelt JS, Ghose R, Dalby KN J Biol Chem. 2025 Oct;301(10):110650. doi: 10.1016/j.jbc.2025.110650. Epub 2025 , Aug 28. PMID:40885389<ref>PMID:40885389</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9ocw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dalby K]]
[[Category: Ghose R]]
[[Category: Isiorho EA]]
[[Category: Long K]]
[[Category: Piserchio A]]