title: Novel motif in calcineurin catalytic subunit is required for septal localization of calcineurin in Aspergillus fumigatus.
abstract: 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.
authors: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
authors: Praveen R
authors: PR
authors: Juvvadi
authors: Duke Macromolecular Crystallography Center, Duke University Medical Center, Durham, NC, USA.
authors: Charles W
authors: CW
authors: Pemble
authors: Department of Dermatology and Venereology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
authors: Yan
authors: Y
authors: Ma
authors: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.|Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
authors: William J
authors: WJ
authors: Steinbach
mesh_terms: D020816:Amino Acid Motifs; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D021984:Cyclophilin A / Q000737:chemistry; D016572:Cyclosporine / Q000737:chemistry; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025301:Hyphae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D055503:Protein Multimerization; D013379:Substrate Specificity; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D005656:Fungal Proteins; D016572:Cyclosporine; D019703:Calcineurin; D021984:Cyclophilin A; D016559:Tacrolimus
keywords: Aspergillus fumigatus; FK506; LxVP motif; PxIxIT motif; calcineurin; septum