Molecular basis of AKAP79 regulation by calmodulin

Nat Commun. 2017 Nov 22;8(1):1681. doi: 10.1038/s41467-017-01715-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A Kinase Anchor Proteins / chemistry*
  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Amino Acid Sequence
  • Binding Sites / genetics
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Calmodulin / chemistry*
  • Calmodulin / genetics
  • Calmodulin / metabolism*
  • Computational Biology
  • Cross-Linking Reagents
  • Crystallography, X-Ray
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • A Kinase Anchor Proteins
  • AKAP5 protein, human
  • Calmodulin
  • Cross-Linking Reagents
  • Recombinant Proteins
  • Calcineurin
  • Calcium