Elongation factor 2 kinase explained

eukaryotic elongation factor-2 kinase
Ec Number:	2.7.11.20
Go Code:	0004686

In enzymology, an elongation factor 2 kinase is an enzyme that catalyzes the chemical reaction:

ATP + [elongation factor 2]

\rightleftharpoons 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.

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.

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]}

Further reading

• Mitsui K, Brady M, Palfrey HC, Nairn AC . Purification and characterization of calmodulin-dependent protein kinase III from rabbit reticulocytes and rat pancreas . J. Biol. Chem. . 268 . 18 . 13422 - 33 . 1993 . 10.1016/S0021-9258(19)38667-3 . 8514778 . free .
• Hincke MT, Nairn AC . Phosphorylation of elongation factor 2 during Ca(2+)-mediated secretion from rat parotid acini . Biochem. J. . 282 . Pt 3 . 877 - 82 . March 1992. 10.1042/bj2820877 . 1372803 . 1130869 .
• Knebel A, Morrice N, Cohen P . A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38δ . EMBO J. . 20 . 16 . 4360 - 9 . 2001 . 11500363 . 125581 . 10.1093/emboj/20.16.4360 .
• Sans MD, Xie Q, Williams JA . Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini . Biochem. Biophys. Res. Commun. . 319 . 1 . 144 - 51 . 2004 . 15158453 . 10.1016/j.bbrc.2004.04.164 .
• Browne GJ, Finn SG, Proud CG . 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 . 14709557 . 10.1074/jbc.M309773200 . free .
• Ryazanov AG . Elongation factor-2 kinase and its newly discovered relatives . FEBS Lett. . 514 . 1 . 26 - 9 . 2002 . 11904175 . 10.1016/S0014-5793(02)02299-8 . free .

Notes and References

1. Ryazanov AG, Shestakova EA, Natapov PG . Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. . Nature . 334 . 6178 . 170–3 . Jul 14, 1988 . 3386756 . 10.1038/334170a0. 1988Natur.334..170R . 4246244 .
2. Heise C, Gardoni F, Culotta L, di Luca M, Verpelli C, Sala C . Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. . Frontiers in Cellular Neuroscience . 8 . 35 . 2014 . 24574971 . 10.3389/fncel.2014.00035 . 3918593. free .
3. 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 . 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 . 22329831 . 10.1021/bi201788e . 3401519.
4. Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, Warthaka M, Brodbelt JS, Ren P, Dalby KN . The molecular mechanism of eukaryotic elongation factor 2 kinase activation. . The Journal of Biological Chemistry . 289 . 34 . 23901–16 . Aug 22, 2014 . 25012662 . 10.1074/jbc.m114.577148 . 4156036. free .
5. Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B . 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 . 22911754 . 10.1371/journal.pone.0041171 . 3401164. 2012PLoSO...741171T . free .
6. Jan 22, 2014. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.. Apoptosis. 19. 1. 241–58. 10.1007/s10495-013-0927-2. 24193916. Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B. 16393302.