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Title: Balanced interactions of calcineurin with AKAP79 regulate Ca 2+-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:
; ; ; ; ; ;  [1];  [2];  [2]
  1. Harvard-Med
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHANIH
OSTI Identifier:
1037481
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Structural & Molecular Biology; Journal Volume: 19; Journal Issue: 2012
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AFFINITY; FASTENING; NERVE CELLS; PEPTIDES; PHOSPHATASES; PROTEINS; TRANSCRIPTION FACTORS

Citation Formats

Li, Huiming, Pink, Matthew D, Murphy, Jonathan G, Stein, Alexander, Dell,, Acqua, Mark L, Hogan, Patrick G, CH-Boston), and Colorado). Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling. United States: N. p., 2012. Web. doi:10.1038/nsmb.2238.
Li, Huiming, Pink, Matthew D, Murphy, Jonathan G, Stein, Alexander, Dell,, Acqua, Mark L, Hogan, Patrick G, CH-Boston), & Colorado). Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling. United States. doi:10.1038/nsmb.2238.
Li, Huiming, Pink, Matthew D, Murphy, Jonathan G, Stein, Alexander, Dell,, Acqua, Mark L, Hogan, Patrick G, CH-Boston), and Colorado). Mon . "Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling". United States. doi:10.1038/nsmb.2238.
@article{osti_1037481,
title = {Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling},
author = {Li, Huiming and Pink, Matthew D and Murphy, Jonathan G and Stein, Alexander and Dell, and Acqua, Mark L and Hogan, Patrick G and CH-Boston) and Colorado)},
abstractNote = {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.},
doi = {10.1038/nsmb.2238},
journal = {Nature Structural & Molecular Biology},
number = 2012,
volume = 19,
place = {United States},
year = {Mon Apr 30 00:00:00 EDT 2012},
month = {Mon Apr 30 00:00:00 EDT 2012}
}