Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12-FK506 in Cryptococcus neoformans.

Published

Journal Article

Calcineurin is a Ca2+-calmodulin-regulated protein phosphatase that is the target of the immunosuppressive drugs cyclosporin A and FK506. Calcineurin is a heterodimer composed of a catalytic A and a regulatory B subunit. In previous studies, the calcineurin A homologue was identified and shown to be required for growth at 37 degrees C and hence for virulence of the pathogenic fungus Cryptococcus neoformans. Here, we identify the gene encoding the calcineurin B regulatory subunit and demonstrate that calcineurin B is also required for growth at elevated temperature and virulence. We show that the FKR1-1 mutation, which confers dominant FK506 resistance, results from a 6 bp duplication generating a two-amino-acid insertion in the latch region of calcineurin B. This mutation was found to reduce FKBP12-FK506 binding to calcineurin both in vivo and in vitro. Molecular modelling based on the FKBP12-FK506-calcineurin crystal structure illustrates how this mutation perturbs drug interactions with the phosphatase target. In summary, our studies reveal a central role for calcineurin B in virulence and antifungal drug action in the human fungal pathogen C. neoformans.

Full Text

Duke Authors

Cited Authors

  • Fox, DS; Cruz, MC; Sia, RA; Ke, H; Cox, GM; Cardenas, ME; Heitman, J

Published Date

  • February 2001

Published In

Volume / Issue

  • 39 / 4

Start / End Page

  • 835 - 849

PubMed ID

  • 11251806

Pubmed Central ID

  • 11251806

International Standard Serial Number (ISSN)

  • 0950-382X

Digital Object Identifier (DOI)

  • 10.1046/j.1365-2958.2001.02295.x

Language

  • eng

Conference Location

  • England