Journal
FEBS LETTERS
Volume 590, Issue 4, Pages 501-508Publisher
WILEY-BLACKWELL
DOI: 10.1002/1873-3468.12075
Keywords
Aspergillus fumigatus; calcineurin; FK506; LxVP motif; PxIxIT motif; septum
Funding
- NIH/NIAID [R01 AI112595-01]
- National Natural Science Foundation of China [81101233]
- Natural Science Foundation for youth in Shanxi province [2010021036-2]
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Calcineurin heterodimer, comprised of the catalytic (CnaA) and regulatory (CnaB) subunits, localizes at the hyphal tips and septa to direct growth, septation, and disease in the human pathogen Aspergillus fumigatus. Here we discovered a novel motif (FMDVF) required for this critical CnaA septal localization, including residues Phe368, Asp370 and Phe372 overlapping the cyclosporine A-cyclophilin A-binding domain, CnaB-binding helix and the FK506-FKBP12-binding pocket. Mutations in adjacent residues Asn367, Trp374, and Ser375 confer FK506 resistance without impacting CnaA septal localization. Modeling A. fumigatus CnaA confirmed that the FMDVF motif forms a bridge between the two known substrate-binding motifs, PxIxIT and LxVP, and concurrent mutations (F368A D370A; F368A F372A) in the FMDVF motif disrupt CnaA-substrate interaction at the septum.
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