Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

Translation is a tightly regulated process that ensures optimal protein quality and enables adaptation to energy/nutrient availability. The alpha-kinase eukaryotic elongation factor 2 kinase (eEF-2K), a key regulator of translation, specifically phosphorylates the guanosine triphosphatase eEF-2, thereby reducing its affinity for the ribosome and suppressing the elongation phase of protein synthesis. eEF-2K activation requires calmodulin binding and autophosphorylation at the primary stimulatory site, T348. Biochemical studies predict a calmodulin-mediated activation mechanism for eEF-2K distinct from other calmodulin-dependent kinases. Here, we resolve the atomic details of this mechanism through a 2.3-angstrom crystal structure of the heterodimeric complex of calmodulin and the functional core of eEF-2K (eEF-2K(TR)). This structure, which represents the activated T348-phosphorylated state of eEF-2K(TR), highlights an intimate association of the kinase with the calmodulin C-lobe, creating an activation spine that connects its amino-terminal calmodulin-targeting motif to its active site through a conserved regulatory element.

Automated summary

Translation is a regulated process that maintains protein quality and adapts to energy/nutrient availability. eEF-2K, a key regulator of translation, phosphorylates eEF-2 to suppress the elongation phase of protein synthesis. Its activation requires calmodulin binding and phosphorylation at a specific site. The crystal structure of the eEF-2K and calmodulin complex reveals the atomic details of this activation mechanism.