title: Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling.
abstract: In hippocampal neurons, the scaffold protein AKAP79 recruits the phosphatase calcineurin to L-type Ca(2+) channels and couples Ca(2+) influx to activation of calcineurin and of its substrate, the transcription factor NFAT. Here we show that an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT, albeit more strongly. A modest decrease in calcineurin-AKAP affinity due to an altered anchoring sequence is compatible with NFAT activation, whereas a further decrease impairs activation. Counterintuitively, increasing calcineurin-AKAP affinity increases recruitment of calcineurin to the scaffold but impairs NFAT activation; this is probably due to both slower release of active calcineurin from the scaffold and sequestration of active calcineurin by 'decoy' AKAP sites. We propose that calcineurin-AKAP79 scaffolding promotes NFAT signaling by balancing strong recruitment of calcineurin with its efficient release to communicate with NFAT.
authors.affiliation: Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Li
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Pink
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Murphy
authors.forename: Alexander
authors.initials: A
authors.lastname: Stein
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hogan
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary
chemical_list: D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D050778:NFATC Transcription Factors; D019703:Calcineurin