Molecular signal processing by eukaryotic elongation factor 2 kinase (eEF-2K)

Translation of mRNA to protein is essential to all life, and is carried out by the ribosome with the assistance of various initiation and elongation factors. The rate and location at which translation occurs is subject to regulation by an intricate network of positive and negative signaling mechanisms. Such regulation allows the cell to respond to changes in external conditions, such as a sudden drop in nutrient availability. In higher eukaryotes, a key component of this regulation is the phosphorylation of elongation factor 2 (eEF-2) - the enzyme which catalyzes ribosome translocation along the mRNA - by eEF-2 kinase (eEF-2K) on Thr56. This event impedes the affinity of eEF-2 for the ribosome and therefore lowers the rate of protein synthesis. The activity of eEF-2K is tightly regulated by upstream signals, including Ca²⁺-calmodulin and post-translational modification. Aberrant regulation of the eEF-2K axis is known in various disease states, including cancer and depression, yet the molecular mechanisms by which eEF-2K processes the multiple signals that communicate with it are poorly defined. This gap in knowledge precludes the rational design of eEF-2Ktargeting treatments which may be effective at treating such diseases. Here, three broad topics are discussed. First, an overview of what is currently known about the structure, function, and regulation of eEF-2K is presented. Second, we elucidate the mechanisms by which eEF-2K integrates signals at the nutrient-sensitive signaling node. Finally, we characterize a highly active form of eEF-2K which provides insight into the potential structure-function relationship of key portions of the enzyme. Taken together, this work is an important step towards a complete description of the biochemical mechanisms by which eEF-2K is regulated by diverse inputsPharmaceutical Science