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J. Biochem, 1993, Vol. 113, No. 3 292-298
© 1993 Japanese Biochemical Society

research-article

FKBP12-FK506 Complex Inhibits Phosphatase Activity of Two Mammalian Isoforms of Calcineurin Irrespective of Their Substrates or Activation Mechanisms11

Hideyuki Mukai*, Takayoshi Kuno*,2, Chang-Duk Chang*, Ben Lane**, Jay R. Luly** and Chikako Tanaka*

*Department of Pharmacology, Kobe University School of Medicine Chuo-ku, Kobe 650
**Immunoscience Research, Pharmaceutical Products Division, Abbott Laboratories Abbott Park, IL 60064-3500, U.S.A.

2To whom correspondence should be addressed.

The interaction of calcineurin (Ca2+/calmodulin-dependent protein phosphatase) with the potent immunosuppressive agent FK506 and its 12 kDa isoform binding protein (FKBP12) was investigated. The FKBP12-FK506 complex inhibited the Ca2+/calmodulin-stimulated phosphatase activity of each of two calcineurin isofonns, which contain either the catalytic subunit A{alpha} or Aß (calcineurin A{alpha} or Aß) of bovine calcineurin. Calcineurin phosphatase activity was inhibited by the FKBP12-FK506 complex irrespective of the substrate or the enzyme activation mechanism. FK506 and FKBP-12 inhibited calcineurin in a concentration-dependent manner, and complete inhibition of the phosphatase activity appeared to require a molar excess of FKBP12-FK506 complex. Immunochemical measurements revealed tissue differences in the concentration of calcineurin, which may be of importance to the selectivity for immunosuppression of all of the biological effects. Direct binding studies with [3H]dihydro-FK506 suggest that the ratio of FKBP12-FK506 complex to calcineurin in vivo when EL2 production is inhibited is well correlated with the ratio when calcineurin phosphatase activity is inhibited in vitro. These results suggest that calcineurin is a relevant cellular target of FK506 when bound to FKBP-12.

1This study was supported by research grants from the Ministry of Education, Science and Culture, and the Ministry of Health and Welfare of Japan.


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