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J. Biol. Chem., Vol. 269, Issue 42, 26431-26437, 10, 1994
NA Clipstone, DF Fiorentino and GR Crabtree
The calcium/calmodulin-regulated phosphatase calcineurin (CN) is the site
of action of the immunosuppressive drugs cyclosporin A (CsA) and FK506. CN
has recently been established as a key signaling enzyme in the T cell
signal transduction cascade and an important regulator of transcription
factors such as NF-AT and OAP/Oct-1, which are involved in the expression
of a number of important T cell early genes. CsA and FK506 act by forming
complexes with their respective intracellular receptors cyclophilin and
FKBP (immunophilins), which can then bind to CN, inhibiting its enzymatic
activity and thereby preventing early gene expression. CN is comprised of
two subunits: a 59-kDa catalytic subunit (CNA), which contains a calmodulin
binding domain and autoinhibitory region, and a 19-kDa intrinsic calcium
binding regulatory subunit (CNB). In this study, we have utilized a series
of deletion mutants of the CNA subunit to investigate the subunit and
molecular requirements that govern the interaction of CN with
drug-immunophilin complexes. The calmodulin binding and autoinhibitory
domains of the CNA subunit were found to be dispensable for the binding of
CN to drug-immunophilin complexes. In contrast, we found that the
regulatory CNB subunit appears to play an obligatory role in this
interaction and have defined an amino acid sequence of the CNA subunit
which forms the binding site for CNB. Although necessary, the CNB subunit
per se is not sufficient to mediate an interaction with drug-immunophilin
complexes; amino acid residues of the CNA subunit, specifically a region
located within the putative catalytic domain, are also required for the
interaction of CN with both FKBP-FK506 and cyclophilin A-CsA.
Molecular analysis of the interaction of calcineurin with drug- immunophilin complexes
Howard Hughes Medical Institute, Stanford University School of Medicine, California 94305.
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