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Molecular basis of AKAP79 regulation by calmodulin

Author

Listed:
  • Neha Patel

    (Physiology & Pharmacology, University College London, Gower Street)

  • Florian Stengel

    (University of Konstanz, Universitätsstrasse 10
    Institute of Molecular Systems Biology, ETH Zürich)

  • Ruedi Aebersold

    (Institute of Molecular Systems Biology, ETH Zürich
    University of Zürich)

  • Matthew G. Gold

    (Physiology & Pharmacology, University College London, Gower Street)

Abstract

AKAP79/150 is essential for coordinating second messenger-responsive enzymes in processes including synaptic long-term depression. Ca2+ directly regulates AKAP79 through its effector calmodulin (CaM), but the molecular basis of this regulation was previously unknown. Here, we report that CaM recognizes a ‘1-4-7-8’ pattern of hydrophobic amino acids starting at Trp79 in AKAP79. Cross-linking coupled to mass spectrometry assisted mapping of the interaction site. Removal of the CaM-binding sequence in AKAP79 prevents formation of a Ca2+-sensitive interface between AKAP79 and calcineurin, and increases resting cellular PKA phosphorylation. We determined a crystal structure of CaM bound to a peptide encompassing its binding site in AKAP79. CaM adopts a highly compact conformation in which its open Ca2+-activated C-lobe and closed N-lobe cooperate to recognize a mixed α/310 helix in AKAP79. The structure guided a bioinformatic screen to identify potential sites in other proteins that may employ similar motifs for interaction with CaM.

Suggested Citation

  • Neha Patel & Florian Stengel & Ruedi Aebersold & Matthew G. Gold, 2017. "Molecular basis of AKAP79 regulation by calmodulin," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01715-w
    DOI: 10.1038/s41467-017-01715-w
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