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

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...

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Bibliographic Details
Published in:Molecular microbiology 2001-02, Vol.39 (4), p.835-849
Main Authors: Fox, Deborah S., Cruz, M. Cristina, Sia, Rey A. L., Ke, Hengming, Cox, Gary M., Cardenas, Maria E., Heitman, Joseph
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Calcineurin - chemistry
Calcineurin - genetics
Calcineurin - metabolism
Cryptococcosis - microbiology
Cryptococcus neoformans
Cryptococcus neoformans - genetics
Cryptococcus neoformans - growth & development
Cryptococcus neoformans - metabolism
Cryptococcus neoformans - pathogenicity
Disease Models, Animal
DNA, Fungal
FK506
FKBP12 gene
FKR1-1 gene
Fungal Proteins - chemistry
Fungal Proteins - genetics
Fungal Proteins - metabolism
Genes, Fungal
Heating
Humans
Mice
Mice, Inbred DBA
Molecular Sequence Data
Mutagenesis
Protein Structure, Secondary
Recombination, Genetic
Sequence Homology, Amino Acid
Tacrolimus - chemistry
Tacrolimus - metabolism
Tacrolimus Binding Protein 1A - chemistry
Tacrolimus Binding Protein 1A - metabolism
Virulence
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Summary: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°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.
ISSN:0950-382X
1365-2958
DOI:10.1046/j.1365-2958.2001.02295.x