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Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin

2016; Elsevier BV; Volume: 24; Issue: 9 Linguagem: Inglês

10.1016/j.str.2016.06.015

1878-4186

Kwangwoon Lee, Sébastien Alphonse, Andrea Piserchio, Clint D.J. Tavares, David H. Giles, Rebecca M. Wellmann, Kevin N. Dalby, Ranajeet Ghose,

Signaling Pathways in Disease

Binding of Ca2+-loaded calmodulin (CaM) activates eukaryotic elongation factor 2 kinase (eEF-2K) that phosphorylates eEF-2, its only known cellular target, leading to a decrease in global protein synthesis. Here, using an eEF-2K-derived peptide (eEF-2KCBD) that encodes the region necessary for its CaM-mediated activation, we provide a structural basis for their interaction. The striking feature of this association is the absence of Ca2+ from the CaM C-lobe sites, even under high Ca2+ conditions. eEF-2KCBD engages CaM largely through the C lobe of the latter in an anti-parallel 1-5-8 hydrophobic mode reinforced by a pair of unique electrostatic contacts. Sparse interactions of eEF-2KCBD with the CaM N lobe results in persisting inter-lobe mobility. A conserved eEF-2K residue (W85) anchors it to CaM by inserting into a deep hydrophobic cavity within the CaM C lobe. Mutation of this residue (W85S) substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells.