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

Piserchio, Andrea; Isiorho, Eta A.; Long, Kimberly; Bohanon, Amanda L.; Kumar, Eric A.; Will, Nathan; Jeruzalmi, David; Dalby, Kevin N.; Ghose, Ranajeet

doi:10.1126/sciadv.abo2039

DOE OSTI · 1982945

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

Piserchio, Andrea·Isiorho, Eta A.·Long, Kimberly·Bohanon, Amanda L.·Kumar, Eric A.·Will, Nathan·Jeruzalmi, David·Dalby, Kevin N.·Ghose, Ranajeet

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Abstract

Translation is a tightly regulated process that ensures optimal protein quality and enables adaptation to energy/nutrient availability. The α-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-Å 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.

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Piserchio, Andrea, Isiorho, Eta A., Long, Kimberly, Bohanon, Amanda L., Kumar, Eric A., Will, Nathan, Jeruzalmi, David, Dalby, Kevin N., Ghose, Ranajeet. 2022-07-06. Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase. https://doi.org/10.1126/sciadv.abo2039

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