Identification of novel interacting regions involving calcineurin and nuclear factor of activated T cells

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Abstract Nuclear factor of activated T cells (NFAT) leads to the transcription of diverse inducible genes involved in many biological processes; therefore, aberrant NFAT expression is responsible for the development and exacerbation of various disorders. Since five isoforms of NFAT (NFATc1‐c4, NFAT5) exhibit distinct and overlapping functions, selective control of a part, but not all, of NFAT family members is desirable. By comparing the binding activity of each NFATc1‐c4 with its regulatory enzyme, calcineurin (CN), using a quantitative immunoprecipitation assay, we found a new CN‐binding region (CNBR) selectively functioning in NFATc1 and NFATc4. This region, termed CNBR3, is located between two preexisting CNBR1 and CNBR2, within the Ca 2+ regulatory domain. The nuclear translocation of NFATc1 but not NFATc2 in T cells was suppressed by ectopic expression of CNBR3 and, accordingly, NFATc1‐dependent cytokine expression was downregulated. Through competition assays using NFATc1‐derived partial peptides and mass spectrometry with photoaffinity technology, we identified 18 amino acids in NFATc1 (Arg 258 to Pro 275 ) and 13 amino acids in CN catalytic subunit (CNA) (Asn 77 to Gly 89 ) responsible for CNA/CNBR3 binding in which Cys 263 and Asp 82 , respectively, played crucial roles. The possible selective regulation of NFAT‐mediated biological processes by targeting this new CN/NFAT‐binding region is suggested.

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