Elongation factor 2 kinase
| eukaryotic elongation factor-2 kinase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 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 | ||||||||
| |||||||||
In enzymology, an elongation factor 2 kinase (EC 2.7.11.20) is an enzyme that catalyzes the chemical reaction:
- ATP + [elongation factor 2] 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
[edit]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
[edit]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
[edit]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
[edit]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
[edit]- ^ 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. Bibcode:1988Natur.334..170R. doi:10.1038/334170a0. PMID 3386756. S2CID 4246244.
- ^ 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.
- ^ a b Tavares CD, O'Brien JP, Abramczyk O, Devkota AK, Shores KS, Ferguson SB, Kaoud TS, Warthaka M, Marshall KD, Keller KM, Zhang Y, Brodbelt JS, Ozpolat B, Dalby KN (Mar 20, 2012). "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. doi:10.1021/bi201788e. PMC 3401519. PMID 22329831.
- ^ a b 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. Bibcode:2012PLoSO...741171T. 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. S2CID 16393302.
Further reading
[edit]- 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. doi:10.1016/S0021-9258(19)38667-3. 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. doi:10.1042/bj2820877. 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.
