Elongation factor 2 kinase
|eukaryotic elongation factor-2 kinase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
- ATP + [elongation factor 2] ADP + [elongation factor 2] phosphate.
This enzyme belongs to the family of transferases, specifically those transferring a phosphate group to the sidechain oxygen atom of serine or threonine residues in proteins (protein-serine/threonine kinases). The systematic name of this enzyme class is "ATP:[elongation factor 2] phosphotransferase". Other names in common use include Ca/CaM-kinase III, calmodulin-dependent protein kinase III, CaM kinase III, eEF2 kinase, eEF-2K, eEF2K, EF2K, and STK19.
The only known physiological substrate of eEF-2K is eEF-2. Phosphorylation of eEF-2 at Thr-56 by eEF-2K leads to inhibition of the elongation phase of protein synthesis. Phosphorylation of Thr-56 is thought to reduce the affinity of eEF-2 for the ribosome, thereby slowing down the overall rate of elongation. However, there is growing evidence to suggest that translation of certain mRNAs is actually increased by phosphorylation of eEF-2 by eEF-2K, especially in a neuronal context.
The activity of eEF-2K is dependent on calcium and calmodulin. Activation of eEF-2K proceeds by a sequential two-step mechanism. First, calcium-calmodulin binds with high affinity to activate the kinase domain, triggering rapid autophosphorylation of Thr-348. In the second step, autophosphorylation of Thr-348 leads to a conformational change in the kinase likely supported by the binding of phospho-Thr-348 to an allosteric phosphate binding pocket in the kinase domain. This increases the activity of eEF-2K against its substrate, elongation factor 2.
eEF-2K can gain calcium-independent activity through autophosphorylation of Ser-500. However, calmodulin must remain bound to the enzyme for its activity to be sustained.
- Ryazanov AG, Shestakova EA, Natapov PG (Jul 14, 1988). "Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation". Nature. 334 (6178): 170–3. doi:10.1038/334170a0. PMID 3386756.
- Heise C, Gardoni F, Culotta L, di Luca M, Verpelli C, Sala C (2014). "Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons". Frontiers in Cellular Neuroscience. 8: 35. doi:10.3389/fncel.2014.00035. PMC 3918593. PMID 24574971.
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- Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, Warthaka M, Brodbelt JS, Ren P, Dalby KN (Aug 22, 2014). "The molecular mechanism of eukaryotic elongation factor 2 kinase activation". The Journal of Biological Chemistry. 289 (34): 23901–16. doi:10.1074/jbc.m114.577148. PMC 4156036. PMID 25012662.
- Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B (Mar 20, 2012). "Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer". PLOS ONE. 7 (7): e41171. doi:10.1371/journal.pone.0041171. PMC 3401164. PMID 22911754.
- Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B (Jan 22, 2014). "Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells". Apoptosis. 19 (1): 241–58. doi:10.1007/s10495-013-0927-2. PMID 24193916.
- Mitsui K, Brady M, Palfrey HC, Nairn AC (1993). "Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas". J. Biol. Chem. 268 (18): 13422–33. PMID 8514778.
- Hincke MT, Nairn AC (March 1992). "Phosphorylation of elongation factor 2 during Ca(2+)-mediated secretion from rat parotid acini". Biochem. J. 282 (Pt 3): 877–82. PMC 1130869. PMID 1372803.
- Knebel A, Morrice N, Cohen P (2001). "A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38δ". EMBO J. 20 (16): 4360–9. doi:10.1093/emboj/20.16.4360. PMC 125581. PMID 11500363.
- Sans MD, Xie Q, Williams JA (2004). "Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini". Biochem. Biophys. Res. Commun. 319 (1): 144–51. doi:10.1016/j.bbrc.2004.04.164. PMID 15158453.
- Browne GJ, Finn SG, Proud CG (2004). "Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398". J. Biol. Chem. 279 (13): 12220–31. doi:10.1074/jbc.M309773200. PMID 14709557.
- Ryazanov AG (2002). "Elongation factor-2 kinase and its newly discovered relatives". FEBS Lett. 514 (1): 26–9. doi:10.1016/S0014-5793(02)02299-8. PMID 11904175.