Eukaryotic elongation factor 2 kinase (eEF2K) is one of the few atypical "a kinase" members. It phosphorylates and inhibits eukaryotic elongation factor 2, thereby slowing the elongation phase of protein synthesis, which usually consumes a lot of energy and amino acids. eEF2K activity usually depends on calcium and calmodulin. eEF2K is also regulated by a number of other input signals, including by suppressing signals downstream of the anabolic signaling pathway, such as mammalian targets of rapamycin complex 1. The latest data show that eEF2K helps protect cancer cells from nutritional starvation and also has cytoprotective effects in other cases, including hypoxia. Increasing evidence shows the role of eEF2K in neurological processes (such as learning and memory) and depression.
eEF2K is an atypical "alpha kinase"
Eukaryotic elongation factor 2 kinase (eEF2K) belongs to a group of atypical protein kinases called "a kinases" and has six members in the human genome. Alpha-kinases have no sequence similarity to the major protein kinase superfamily, although they do show limited three-dimensional structural similarity. eEF2K is the only alpha kinase whose activity depends on Ca2+ ions. The only known substrate for eEF2K is eExtender eEF2. Little is known about the regulation of the activities of the other five family members or their substrates. Because phosphorylation of eEF2 at Thr56 weakens its binding to the ribosome, eEF2K acts to inhibit eEF2, thereby slowing the extension rate. This residue is very conserved with adjacent sequences, even in germinating yeast. However, eEF2K homologs are not available in many places. Eukaryotes, such as fungi, plants and arthropods. The eEF2 homologs found in nematodes and yeast can be phosphorylated on the equivalent Thr56 by different kinases Rck2. Calmodulin (CaM) confers Ca2+ ions to activate eEF2K. Calmodulin (CaM) binds up to four Ca2+ ions and interacts with regions near the N-terminus of its catalytic domain in eEF2K. The mechanism by which Ca2+/CaM activates eEF2K is unknown. In some other Ca/CaM kinases, activation occurs as a result of removing the self-suppressing helix feature from the active site. However, it is unclear whether eEF2K contains this regulatory motif. The overall layout of eEF2K is shown in Figure 1. The removal of a region of approximately 80 residues at the N-terminus of the CaM binding motif can enhance eEF2K activity, suggesting that it may play a regulatory role. The catalytic domain contains approximately 125-320 residues in human eEF2K. The C-terminus is the autophosphorylation site required for activity (Thr348). In Dictyostelium discoideum myosin heavy chain kinase A (MHCK A), the corresponding residue in another alpha kinase (also a self-phosphorylated threonine) apparently stops at "phosphate-binding Bag" to help produce an active conformation. Sequence alignment indicates that a similar mechanism may be applicable to eEF2K. eEF2K is also autophosphorylated at other sites, including Ser445 and Ser500 in a report.
Controlling the stability of eEF2K
The eEF2K protein is degraded by proteasome-dependent pathways during normal oxygenation of breast cancer cells or in response to the inhibition of hsp90, and the inhibition of hsp90 acts as a partner for eEF2K. After genotoxic stress, eEF2K is activated and subsequently degraded again through a proteasome-dependent mechanism. These authors show that this degradation requires ubiquitin ligase SCF (bTrCP) (Skp1-Cul1-Fbox protein, a protein containing b-transducer repeats). Some people believe that the rapid activation of eEF2K can provide a transient slowdown in protein synthesis. The later degradation of eEF2K requires the cells to re-enter the cell cycle. In this case, the degradation of eEF2K requires an autophosphorylation site at Ser445, which forms part of a typical bTrCP binding motif or phosphate dehydroribonucleic acid. Considering that such motifs usually contain two phosphate residues, it is likely that Ser441 phosphorylation of eEF2K will also be degraded by this mechanism. In many cases, transient activation of eEF2K is observed and subsequently degraded, resulting in a decrease in eEF2 phosphorylation. Further work is needed to understand the transiently increasing function of eEF2 phosphorylation.
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