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J. Biol. Chem., Vol. 268, Issue 19, 14040-14044, Jul, 1993
W Li and RE Handschumacher
Calcineurin (CaN), a Ca2+/calmodulin-dependent serine/threonine
phosphatase, has been shown to be inhibited by the complex of the
immunosuppressant cyclosporin A (CsA) and its receptor, cyclophilin (CyP),
but not by either alone. In the current study, the topological relationship
between cyclophilin and the subunits of CaN has been explored using
chemical cross-linking agents. In the presence of cyclosporin, 125I-CyP,
shown to bind to CsA, is extensively cross- linked to the B subunit of CaN
but not the catalytic A subunit. However, the A subunit is required for
binding of the CyP.CsA complex, since cross-linking to recombinant B
subunit alone does not occur. The kinetics of association indicate a
saturable reaction with a Kd of less than 70 nM. Cross-linking to the B
subunit occurs with cross-linkers that span from 0 to 16 A and employ
different cross-linking chemistry, indicating direct contact between the B
subunit and CyP. Similar cross- linking to the B subunit has been observed
with the complex of 125I- labeled FK506 binding protein (FKBP) and FK506
but not with the FKBP- rapamycin complex. CyP.CsA cross-linking to CaN is
Ca2+/calmodulin- dependent with intact CaN, but Ca2+/calmodulin-independent
after digestion to remove the calmodulin binding and autoinhibitory domain.
Specific interaction of the cyclophilin-cyclosporin complex with the B subunit of calcineurin
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
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