THE LATCH REGION OF CALCINEURIN-B IS INVOLVED IN BOTH IMMUNOSUPPRESSANT-IMMUNOPHILIN COMPLEX DOCKING AND PHOSPHATASE ACTIVATION

The immunosuppressants cyclosporin A and FK506, when complexed with th eir intracellular receptors, prevent T cell activation by directly bin ding to the phosphatase calcineurin. We have used molecular modeling a nd mutagenesis to identify sites on calcineurin important for this int eraction. We have created calcineurins that are resistant to both cycl osporin A and FK506 by mutating specific residues in CnB, a calcium-bi nding protein that regulates the catalytic subunit, CnA. Significantly , on a model of CnB, these mutations map to the latch region, an eleme nt of tertiary structure that forms when CnB binds CnA. In addition, w e show that this latch region plays an important role in activating th e catalytic subunit CnA. These results suggest a molecular mechanism f or suppression of calcineurin by cyclosporin A and FK506 involving the ir binding to the same region of CnB used for allosterically activatin g CnA.