Novel motif in calcineurin catalytic subunit is required for septal localization of calcineurin in Aspergillus fumigatus

FEBS Lett. 2016 Feb;590(4):501-8. doi: 10.1002/1873-3468.12075. Epub 2016 Feb 15.


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.

Keywords: Aspergillus fumigatus; FK506; LxVP motif; PxIxIT motif; calcineurin; septum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Aspergillus fumigatus / drug effects
  • Aspergillus fumigatus / genetics
  • Aspergillus fumigatus / metabolism*
  • Calcineurin / chemistry
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Catalytic Domain*
  • Cyclophilin A / chemistry
  • Cyclosporine / chemistry
  • Drug Resistance, Fungal
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Hyphae / drug effects
  • Hyphae / genetics
  • Hyphae / metabolism*
  • Molecular Sequence Data
  • Mutation
  • Protein Multimerization
  • Substrate Specificity
  • Tacrolimus / pharmacology


  • Fungal Proteins
  • Cyclosporine
  • Calcineurin
  • Cyclophilin A
  • Tacrolimus