INTERACTION OF FKBP12-FK506 WITH CALCINEURIN-A AT THE B-SUBUNIT-BINDING DOMAIN

被引:37
作者
KAWAMURA, A [1 ]
SU, MSS [1 ]
机构
[1] VERTEX PHARMACEUT INC,CAMBRIDGE,MA 02139
关键词
D O I
10.1074/jbc.270.26.15463
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
Calcineurin is a calcium-dependent protein phosphatase that plays a pivotal role in antigen stimulated T cell activation, The complexes formed between the immunosuppressants cyclosporin A and FH506 and their respective intracellular binding proteins (immunophilins) block T cell activation by binding to calcineurin, Recent studies have shown that the immunophilin-immunosuppressant complexes interact with the latch region of the calcineurin B subunit (Milan, D,, Griffith, J,, Su, M., Price, E, R,, and McKeon, F, (1994) Cell 79, 437-447), Mutations in the B subunit-binding domain of the calcineurin A subunit result in a reduction of calcineurin activity that correlates with B binding affinity, Calcineurin A subunit mutants D348A, F350A, W352A, S353A, and E359A lost greater than 90% of their activity to activate the transcription factor NF kappa B in Jurkat T cells, Furthermore, calcineurin A subunit mutants of residues Thr(351), Leu(354) and Lys(360) showed NF kappa B transactivation activity and phosphatase activity with increased resistance to FKBP12-FK506 but displayed no or minimal increase in resistance for cyclosporin A inhibition, Together, these results strongly suggest that the E subunit-binding domain is required for calcineurin activity intracellularly and interacts with the FKBP12-FK506 complex.
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页码:15463 / 15466
页数:4
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