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

被引:104
作者
MILAN, D
GRIFFITH, J
SU, M
PRICE, ER
MCKEON, F
机构
[1] HARVARD UNIV,SCH MED,DEPT CELL BIOL,BOSTON,MA 02115
[2] VERTEX PHARMACEUT,CAMBRIDGE,MA 02139
关键词
D O I
10.1016/0092-8674(94)90253-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The immunosuppressants cyclosporin A and FK506, when complexed with their intracellular receptors, prevent T cell activation by directly binding to the phosphatase calcineurin. We have used molecular modeling and mutagenesis to identify sites on calcineurin important for this interaction. We have created calcineurins that are resistant to both cyclosporin A and FK506 by mutating specific residues in CnB, a calcium-binding protein that regulates the catalytic subunit, CnA. Significantly, on a model of CnB, these mutations map to the latch region, an element of tertiary structure that forms when CnB binds CnA. In addition, we show that this latch region plays an important role in activating the catalytic subunit CnA. These results suggest a molecular mechanism for suppression of calcineurin by cyclosporin A and FK506 involving their binding to the same region of CnB used for allosterically activating CnA.
引用
收藏
页码:437 / 447
页数:11
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