Balanced interactions of calcineurin with AKAP79 regulate Ca²⁺-calcineurin-NFAT signaling

Journal Article · Mon Apr 30 04:00:00 EDT 2012 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/nsmb.2238· OSTI ID:1037481

Li, Huiming; Pink, Matthew D; Murphy, Jonathan G; Stein, Alexander; Dell,; Acqua, Mark L; Hogan, Patrick G ^[1]

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1. Harvard-Med

In hippocampal neurons, the scaffold protein AKAP79 recruits the phosphatase calcineurin to L-type Ca²⁺ channels and couples Ca²⁺ 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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: AHANIH
• OSTI ID: 1037481
• Journal Information: Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 2012 Vol. 19; ISSN 1545-9993
• Publisher: Nature Publishing Group
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AFFINITY
FASTENING
NERVE CELLS
PEPTIDES
PHOSPHATASES
PROTEINS
TRANSCRIPTION FACTORS