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Literature summary for 2.7.11.20 extracted from
- Eukaryotic elongation factor 2 kinase, an unusual enzyme with multiple roles (2014), Adv. Biol. Regul., 55, 15-27.
Activating Compound
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| Calmodulin | required | Homo sapiens |  |
| Calmodulin | required | Mus musculus | |
| additional information | AMP-activated protein kinase, AMPK, a major sensor of (low) cellular energy status stimulates the activity of eEF2K via phosphorylation of Ser500 | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | generation of eEF2K knockout mice and eEF2K knock-in mice, phenotype, overview | Mus musculus |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 7-amino-1-cyclopropyl-3-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-pyrido[2,3-d]pyrimidine-6-carboxamide | inhibits eEF2 phosphorylation in cells as well as in vitro | Mus musculus | |
| 7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carboxamide | inhibits eEF2 phosphorylation in cells as well as in vitro | Homo sapiens | |
| additional information | eEF2K activity is also regulated by phosphorylation. Ser366 is phosphorylated by S6 kinases, enzymes which are phosphorylated and activated by mTORC1, phosphorylation at this site desensitizes eEF2K to activation by Ca2+/CaM. Phosphorylation of Ser359, a site whose modification strongly inhibits eEF2K, and Ser78, immediately next to the CaM-binding motif, are also promoted by mTORC1. The latter strongly impairs the interaction of eEF2K with CaM thereby impairing its activation | Homo sapiens | |
| rottlerin | unspecific inhibition | Homo sapiens | |
| rottlerin | unspecific inhibition | Mus musculus | |
| TX-1123 | inhibits eEF2K, but also affects the activity of tyrosine kinases and exhibits mitochondrial toxicity | Homo sapiens | |
| TX-1123 | inhibits eEF2K, but also affects the activity of tyrosine kinases and exhibits mitochondrial toxicity | Mus musculus | |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | required | Homo sapiens | |
| Ca2+ | required | Mus musculus | |
| Mg2+ | required | Homo sapiens | |
| Mg2+ | required | Mus musculus | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + [elongation factor 2] | Homo sapiens | - |
ADP + [elongation factor 2] phosphate | - |
? | |
| ATP + [elongation factor 2] | Mus musculus | - |
ADP + [elongation factor 2] phosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
- |
- |
| Mus musculus | O08796 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | eEF2K activity is also regulated by phosphorylation. Ser366 is phosphorylated by S6 kinases, enzymes which are phosphorylated and activated by mTORC1, phosphorylation at this site desensitizes eEF2K to activation by Ca2+/CaM. Phosphorylation of Ser359, a site whose modification strongly inhibits eEF2K, and Ser78, immediately next to the CaM-binding motif, are also promoted by mTORC1. The latter strongly impairs the interaction of eEF2K with CaM thereby impairing its activation. For eEF2K stimulation, cAMP, a catabolic signal which inhibits protein synthesis, stimulates cAMP-dependent protein kinase, PKA, which phosphorylates eEF2K at Ser500. Degradation of eEF2K requires the autophosphorylation site at Ser445, which forms part of a typical bTrCP-binding motif or phosphodegron. eEF2K is also phosphorylated at several sites in response to activation of stress-stimulated MAP kinase cascades, either directly by MAPKs or by their downstream effectors. Phosphorylation of eEF2 at Thr56 impairs its binding to the ribosome. The enzyme is regulated by its phosphorylation status, overview | Homo sapiens |
| phosphoprotein | the enzyme is phosphorylated by diverse kinases with stimulating or suppressing effect, the enzyme is regulated by its phosphorylation status, overview | Mus musculus |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | - |
Homo sapiens | - |
| brain | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + [elongation factor 2] | - |
Homo sapiens | ADP + [elongation factor 2] phosphate | - |
? | |
| ATP + [elongation factor 2] | - |
Mus musculus | ADP + [elongation factor 2] phosphate | - |
? | |
| additional information | the enzyme performs autophosphorylation | Mus musculus | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | domain structure and regulation of eEF2K, overview | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| eEF2K | - |
Homo sapiens |
| eEF2K | - |
Mus musculus |
| eukaryotic elongation factor 2 kinase | - |
Homo sapiens |
| eukaryotic elongation factor 2 kinase | - |
Mus musculus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Homo sapiens | |
| ATP | - |
Mus musculus | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical alpha-kinases, eEF2K is not a member of the main kinase superfamily. alpha-Kinases show no sequence similarity to the main protein kinase superfamily, although they do display limited three-dimensional structural similarity | Homo sapiens |
| evolution | eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical alpha-kinases, eEF2K is not a member of the main kinase superfamily. alpha-Kinases show no sequence similarity to the main protein kinase superfamily, although they do display limited three-dimensional structural similarity | Mus musculus |
| malfunction | eEF2K-knockout mice are viable and fertile under standard vivarium conditions. mGluR-induced long-term depression (LTD), but not LTD induced by other stimuli, is impaired in eEF2K knockout mice. The memory deficits in eEF2K knock-in mice are due to sleep-related alterations. Fear-conditioning responses in mice are deficient in eEF2K activity | Mus musculus |
| malfunction | knocking down eEF2K in hippocampal neurons inhibits synaptic activity induced increases in BDNF production and decreases the stability of dendritic spines | Homo sapiens |
| metabolism | the eEF2K protein is degraded via a proteasome-dependent pathway | Mus musculus |
| metabolism | the eEF2K protein is degraded via a proteasome-dependent pathway, e.g., during normoxia in breast cancer cells or in response to inhibition of hsp90, which acts as a chaperone for eEF2K. Degradation of eEF2K requires the autophosphorylation site at Ser445, which forms part of a typical bTrCP-binding motif or phosphodegron | Homo sapiens |
| physiological function | eEF2K appears to be a non-essential gene | Mus musculus |
| physiological function | eEF2K phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids.. eEF2K is dependent on Ca2+ and calmodulin, and is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Enzyme eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Roles for eEF2K in neurological processes such as learning and memory and perhaps in depression. Regulation by phosphorylation of eukaryotic elongation factor 2 (eEF2), overview. In addition to being dependent upon Ca2+/calmodulin, eEF2K activity is also regulated by phosphorylation, which occurs at several sites downstream of various signalling pathways. eEF2K activity is negatively regulated by signalling through the mammalian target of rapamycin complex 1 (mTORC1). Consequence of increasing eEF2K activity in the brain may be to regulate the synthesis of specific proteins. Increases in eEF2K activity are important for the synthesis of Arc, an immediate-early gene involved in the trafficking of glutamate receptors and cytoskeletal rearrangement that is implicated in various types of synaptic plasticity and memory. Stimulation of metabotropic glutamate receptors (mGluRs) results in an eEF2Kdependent increase in Arc synthesis | Homo sapiens |
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