FKBP12 BINDS THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR AT LEUCINE-PROLINE-(1400-1401) AND ANCHORS CALCINEURIN TO THIS FK506-LIKE DOMAIN

The immunophilin FKBP12 is one of the most abundant and conserved prot eins in biology. It is the primary receptor for the immunosuppressant actions of the drug FK506 in whose presence FKBP12 binds to and inhibi ts calcineurin, disrupting interleukin formation in lymphocytes. The p hysiologic functions of FKBP12 are less clear, although the protein ha s been demonstrated to physiologically interact with the inositol 1,4, 5-trisphosphate receptor (IP3R), the ryanodine receptor, and the type 1 transforming growth factor beta receptor. We now report that FKBP12 binds the IP3R at residues 1400-1401, a leucyl-prolyl dipeptide epitop e that structurally resembles FK506. We further demonstrate that bindi ng to IP3R at this site enables FKBP12 to interact with calcineurin, p resumably to anchor the phosphatase to IP3R and modulate the receptor' s phosphorylation status. We propose that FK506 promotes an FKBP12-cal cineurin interaction by mimicking structurally similar dipeptide epito pes present within proteins that use FKBP12 to anchor calcineurin to t he appropriate physiologic substrates.