Journal
MOLECULAR CELL
Volume 25, Issue 6, Pages 889-901Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2007.02.014
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Funding
- NIAID NIH HHS [AI40127, R01 AI040127] Funding Source: Medline
- NIGMS NIH HHS [R01 GM048729, R01 GM048729-17, R01 GM048729-18, GM-48728] Funding Source: Medline
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Calcineurin, the conserved Ca2+/calmodulin-regulated protein phosphatase, mediates diverse aspects of Ca2+-dependent signaling. We show that substrates bind calcineurin with varying strengths and examine the impact of this affinity on signaling. We altered the calcineurin-docking site, or PxIxIT motif, in Crz1, the calcineurin-regulated transcription factor in S. cerevisiae, to decrease (Crz1(PVIAVN)) or increase (Crz1(PVIVIT)) its affinity for calcineurin. As a result, the Ca2+-dependent dephosphorylation and activation of Crz1(PVIAVN) are decreased, whereas Crz1(PVIVIT) is constitutively dephosphorylated and hyperactive. Surprisingly, the physiological consequences of altering calcineurin-Crz1 affinity depend on the growth conditions. Crz1(PVIVIT) improves yeast growth under several environmental stress conditions but causes a growth defect during alkaline stress, most likely by titrating calcineurin away from other substrates or regulators. Thus, calcineurin-substrate affinity determines the Ca2+ concentration dependence and output of signaling in vivo as well as the balance between different branches of calcineurin signaling in an overall biological response.
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