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Cyclolinopeptide A (CLA) mediates its immunosuppressive activity through cyclophilin‐dependent calcineurin inactivation
Author(s) -
Gaymes Terry J,
Cebrat Marek,
Siemion Ignacy Z,
Kay John E
Publication year - 1997
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(97)01345-8
Subject(s) - cyclophilin , calcineurin , fkbp , cyclophilin a , peptidylprolyl isomerase , phosphatase , isomerase , chemistry , biochemistry , in vitro , pin1 , tryptophan , microbiology and biotechnology , biology , enzyme , transplantation , medicine , amino acid , gene
The immunosuppressive cyclic nonapeptide cyclolinopeptide A inhibits calcium‐dependent, but not calcium‐independent, activation of T lymphocytes comparably to the actions of cyclosporin A and FK506. The concentration required for complete inhibition, however, is 10 times higher than that of cyclosporin A. In addition, we demonstrate that calcineurin, a phosphatase which plays an important role in T lymphocyte signalling, is inhibited in vitro by cyclolinopeptide A by a mechanism dependent on the peptidyl‐prolyl cis‐trans isomerase (PPIase) cyclophilin A but not FKBP12. Direct binding of cyclolinopeptide A to cyclophilin A was confirmed using tryptophan fluorescence studies and PPIase assays. These results represent a third example of the production of a natural product that neutralises calcineurin by a mechanism dependent on the primary binding to a PPIase.