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Structure. 2016 Sep 6;24(9):1441-51. doi: 10.1016/j.str.2016.06.015. Epub 2016 Aug 4.

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

Author information

1
Department of Chemistry and Biochemistry, The City College of New York, New York, NY 10031, USA; Graduate Program in Biochemistry, The Graduate Center of CUNY, New York, NY 10016, USA.
2
Department of Chemistry and Biochemistry, The City College of New York, New York, NY 10031, USA.
3
Graduate Program in Cell and Molecular Biology, University of Texas, Austin, TX 78712, USA.
4
Division of Chemical Biology and Medicinal Chemistry, University of Texas, Austin, TX 78712, USA.
5
Graduate Program in Cell and Molecular Biology, University of Texas, Austin, TX 78712, USA; Division of Chemical Biology and Medicinal Chemistry, University of Texas, Austin, TX 78712, USA.
6
Department of Chemistry and Biochemistry, The City College of New York, New York, NY 10031, USA; Graduate Program in Biochemistry, The Graduate Center of CUNY, New York, NY 10016, USA; Graduate Program in Chemistry, The Graduate Center of CUNY, New York, NY 10016, USA; Graduate Program in Physics, The Graduate Center of CUNY, New York, NY 10016, USA. Electronic address: rghose@ccny.cuny.edu.

Abstract

Binding of Ca(2+)-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 Ca(2+) from the CaM C-lobe sites, even under high Ca(2+) 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.

PMID:
27499441
PMCID:
PMC5014583
DOI:
10.1016/j.str.2016.06.015
[Indexed for MEDLINE]
Free PMC Article

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