Cyclolinopeptide A (CLA) mediates its immunosuppressive activity through cyclophilin-dependent calcineurin inactivation

Terry J. Gaymes, Marek Cebrat, Ignacy Z. Siemion, John E. Kay

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)224-227
Number of pages4
JournalFEBS Letters
Volume418
Issue number1-2
DOIs
StatePublished - Nov 24 1997
Externally publishedYes

Keywords

  • Calcineurin
  • Cyclolinopeptide A
  • Cyclophilin A
  • Peptidyl-prolyl cis-trans isomerase
  • T lymphocyte activation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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