Structural Delineation of the Calcineurin–NFAT Interaction and its Parallels to PP1 Targeting Interactions

Calcineurin is a phosphoprotein phosphatase that channels intracellular Ca signals into multiple biological pathways. Calcineurin is known to interact directly with its substrate nuclear factor of activated T cells (NFAT or NFATc), with other substrates, and with several targeting and scaffold proteins including AKAP79 and Cabin1/cain. The calcineurin–NFAT interaction depends on recognition of a PxIxIT sequence motif present in NFAT-family proteins and in certain other calcineurin-interacting proteins. Here, we define the structural basis for the interaction of calcineurin with NFAT and with other proteins possessing the PxIxIT motif. The calcineurin–PxIxIT contact has a direct parallel in the contact of protein phosphatase 1 with its regulatory proteins, suggesting that the evolution of these related phosphatases involved local remodelling of an ancestral docking site.