Elongation factor 2 kinase

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eukaryotic elongation factor-2 kinase
Identifiers
EC number2.7.11.20
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / 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]

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.

Further reading[edit]