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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.

SUBMITTER: Li H

PROVIDER: S-EPMC3294036 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Li Huiming H Pink Matthew D MD Murphy Jonathan G JG Stein Alexander A Dell'Acqua Mark L ML Hogan Patrick G PG

Nature structural & molecular biology 20120219 3

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 activat ...[more]

PMID: 22343722

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

Publications

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

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