Novel motif in calcineurin catalytic subunit is required for septal localization of calcineurin in Aspergillus fumigatus
Novel motif in calcineurin catalytic subunit is required for septal localization of calcineurin in Aspergillus fumigatus
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DOI：
10.1002/1873-3468.12075
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发表时间：
2016-02-01
期刊：
影响因子：
3.5
通讯作者：
Steinbach, William J.
中科院分区：
文献类型：
--
作者：
Juvvadi, Praveen R.;Pemble, Charles W.;Steinbach, William J.
钙调神经磷酸酶异二聚体由催化亚基(CNAA)和调节亚基(Cna B)组成，定位于菌丝末端和菌丝隔膜，指导人类病原菌烟曲霉菌的生长、隔膜和疾病。在这里，我们发现了这个关键的CNAA间隔定位所需的新基序(FMDVF)，包括与环孢素A-亲环素A结合结构域、CNAB结合螺旋和FK506-FKBP12结合口袋重叠的Phe368、Asp370和Phe372残基。邻近残基Asn367、Trp374和Ser375的突变赋予FK506耐药性，而不影响CNAA间隔定位。对烟曲霉菌CNAA的建模证实，FMDVF基序在两个已知的底物结合基序PxIxIT和LxVP之间建立了桥梁，FMDVF基序中的并发突变(F368A D370A；F368A F372A)中断了CNAA与底物在隔膜上的相互作用。
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.