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Molecular basis of AKAP79 regulation by calmodulin.


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 ?/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.

SUBMITTER: Patel N 

PROVIDER: S-EPMC5698441 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Molecular basis of AKAP79 regulation by calmodulin.

Patel Neha N   Stengel Florian F   Aebersold Ruedi R   Gold Matthew G MG  

Nature communications 20171122 1


AKAP79/150 is essential for coordinating second messenger-responsive enzymes in processes including synaptic long-term depression. Ca<sup>2+</sup> 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-bindi  ...[more]

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