Biology:Elongation factor 2 kinase
| eukaryotic elongation factor-2 kinase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC number | 2.7.11.20 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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In enzymology, an elongation factor 2 kinase (EC 2.7.11.20) is an enzyme that catalyzes the chemical reaction:
- ATP + [elongation factor 2] [math]\displaystyle{ \rightleftharpoons }[/math] ADP + [elongation factor 2] phosphate.
Thus, the two substrates of this enzyme are ATP and elongation factor 2, whereas its two products are adenosine diphosphate (ADP) and elongation factor 2 phosphate.
Nomenclature
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.
Function
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.[1] 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.[2]
Activation
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.[3][4] 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.[4]
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.[3]
Cancer
eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis.[5][6]
References
- ↑ "Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation.". Nature 334 (6178): 170–3. Jul 14, 1988. doi:10.1038/334170a0. PMID 3386756. Bibcode: 1988Natur.334..170R.
- ↑ "Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons.". Frontiers in Cellular Neuroscience 8: 35. 2014. doi:10.3389/fncel.2014.00035. PMID 24574971.
- ↑ 3.0 3.1 "Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence.". Biochemistry 51 (11): 2232–45. Mar 20, 2012. doi:10.1021/bi201788e. PMID 22329831.
- ↑ 4.0 4.1 "The molecular mechanism of eukaryotic elongation factor 2 kinase activation.". The Journal of Biological Chemistry 289 (34): 23901–16. Aug 22, 2014. doi:10.1074/jbc.m114.577148. PMID 25012662.
- ↑ "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. Mar 20, 2012. doi:10.1371/journal.pone.0041171. PMID 22911754. Bibcode: 2012PLoSO...741171T.
- ↑ "Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.". Apoptosis 19 (1): 241–58. Jan 22, 2014. doi:10.1007/s10495-013-0927-2. PMID 24193916.
Further reading
- "Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas". J. Biol. Chem. 268 (18): 13422–33. 1993. doi:10.1016/S0021-9258(19)38667-3. PMID 8514778.
- "Phosphorylation of elongation factor 2 during Ca(2+)-mediated secretion from rat parotid acini". Biochem. J. 282 (Pt 3): 877–82. March 1992. doi:10.1042/bj2820877. PMID 1372803.
- "A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38δ". EMBO J. 20 (16): 4360–9. 2001. doi:10.1093/emboj/20.16.4360. PMID 11500363.
- "Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini". Biochem. Biophys. Res. Commun. 319 (1): 144–51. 2004. doi:10.1016/j.bbrc.2004.04.164. PMID 15158453.
- "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. 2004. 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.
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