Representative Proteins

At present there are a number of homologues for eukaryotic elongation factor 2 kinase across a number of species. However a vast majority of entries on the NCBI database had not been subjected to a full review and therefore exist as initial records with a ‘PROVISIONAL’, ‘PREDICTED’, or ‘INFERRED’ status. To ensure as much sequence accuracy as possible, only isoforms which have been subjected to a full review were used. The general mechanism and function of the selected represented proteins stay largely consistent across the homologues. In this instance the human isoform has been used to provide a comprehensive overview, with variations in subsequent isoforms highlighted later.

Phylogenetic tree using MAFFT

MSA tool that uses Fast Fourier Transforms.

Eukaryotic Elongation Factor 2 Kinase [Homo sapiens]

Length: 725 amino acids

Gene location: chromosome 16

Catalytic activity: ATP + [elongation factor 2] = ADP + [elongation factor 2] phosphate

The human isozyme of the eEFK2K protein contains a Calmodulin-like binding domain and is dependent on both Calmodulin and Ca2+. It

inhibits eEF2 by phosphorylation, which in turn slows down translation elongation. The kinase composition includes an N-terminal catalytic domain, an alpha helical domain at the C-terminus and a linker with multiple phosphorylation sites which are controlled by mTOR. It is regulated by multiple upstream signalling pathways involving kinases such as AMPK or TRPM7. Activation occurs by an allosteric mechanism whereby 2 sequential conformations occur. First, Ca2+ and Calmodulin bind, which makes it easier for Threonine-348 to be auto phosphorylated. Phospho-Threonine-348 then binds a conserved basic pocket in the kinase domain, which is thought to cause a conformational change in the R-loop, which increases substrate phosphorylation efficiency.

There is also a shared motif between the eEF2K in different species: the GXGXXG motif (nucleotide binding site) which forms the glycine rich loop involved in ATP-binding. This loop is normally found in N-terminal region, but for eEF2K, it is situated at the C-terminal end of the catalytic domain

Eukaryotic Elongation Factor 2 Kinase [Mus musculus]

Length: 724 amino acids

Gene location: chromosome 7 F3

Other: eEF2 is ubiquitously expressed, but a higher abundance is found in the skeletal muscle and the heart, suggesting it is of greater importance here and its substrate is muscle tissue-specific. Unlike normal kinases, eEFK2 lacks the essential Lys-72 which interacts with invariant phosphate groups of ATP. Instead, it is postulated that it interacts via two conserved cysteine residues which might be involved in ATP binding, through a similar mechanism to BCR-ABL protein kinase. These are thought to be Cys-313 and Cys-317 in mouse eEF-2 kinase.

Eukaryotic Elongation Factor 2 Kinase [Rattus norvegicus]

Length: 724 amino acids

Gene location: chromosome 1q35

Other: Autophosphorylated at multiple residues, Thr-347 being the major site. Phosphorylated by AMP-activated protein kinase AMPK at Ser-397 leading to EEF2K activation and protein synthesis inhibition. Phosphorylated by TRPM7 at Ser-77 resulting in improved protein stability, higher EE2F phosphorylated and subsequently reduced rate of protein synthesis. Phosphorylation by other kinases such as CDK1 and MAPK13 at Ser-358 or RPS6KA1 and RPS6KB1 at Ser-365 instead decrease EEF2K activity and promote protein synthesis (By similarity).

Eukaryotic Elongation Factor 2 Kinase [Xenopus tropicalis]

Length: 718 amino acids

Gene location: unknown

Eukryotic Elongation Factor 2 Kinase [Bos Taurus]

Length: 723 amino acids

Gene location: chromosome 25

Eukaryotic Elongation Factor 2 Kinase EFK-1A and 1B Isoforms [Caenorhabditis elegans]

Length: 768 amino acids (1A), 760 amino acids (1B)

Gene location: chromosome III

Other: The Genome of the nematode Caenorhabditis elegans contains over 19,000 genes. More than 40 percent of the predicted protein products find significant matches in other organisms, for this reason their genome is considered a focus for molecular biology, and thus we chose to analyse its isoforms. eEf2 Phosphorylates 2 adjacent threonine residues, 'Thr-57' and 'Thr-59'. Metabolic adaptation is essential for cell survival during nutrient deprivation, eEF2K confers cell survival under acute nutrient depletion by blocking translation elongation. C. elegans strains deficient in eEF2K have been found to be severely compromised in their response to nutrient withdrawal.