Barthelmess I B, Tropschug M
Institut für Angewandte Genetik, Universität Hannover, Federal Republic of Germany.
Curr Genet. 1993 Jan;23(1):54-8. doi: 10.1007/BF00336750.
Growth of Neurospora crassa wild-type is inhibited by micromolar concentrations of the immunosuppressive macrolide FK506. Spontaneous and induced mutations that confer resistance to FK506 identified two loci, fkr-1 and fkr-2. They map on the right arm of linkage group V on either side of inl with fkr-1 being centromere proximal. Allele fb (fkr-2) lacks immunodetectable N. crassa FK506-binding protein (NcFKBP). This demonstrates that the sensitivity of N. crassa towards FK506 is mediated by NcFKBP. FK506-binding proteins have been shown to be highly conserved, i.e., found in all eukaryotic cells tested, and to exhibit peptidyl-prolyl cis-trans isomerase (PPIase) activity in vitro. Possible functions for the loci are discussed. Apart from the resistance to FK506 no other mutant phenotype was detected not even in double mutants that lacked NcFKBP as well as cyclophilin. Cyclophilin mediates the cytotoxic effect of the immunosuppressive drug Cyclosporin A and is also characterized by PPIase activity in vitro. Both FK506-resistant alleles studied exhibit incomplete dominance in forced heterokaryons. A mechanism is proposed to explain this dominance especially in view of the NcFKBP-deficient allele, fb.
免疫抑制性大环内酯类药物FK506的微摩尔浓度可抑制粗糙脉孢菌野生型的生长。赋予对FK506抗性的自发和诱导突变鉴定出两个基因座，fkr-1和fkr-2。它们定位于V连锁群右臂上inl两侧，fkr-1靠近着丝粒。等位基因fb（fkr-2）缺乏可免疫检测到的粗糙脉孢菌FK506结合蛋白（NcFKBP）。这表明粗糙脉孢菌对FK506的敏感性是由NcFKBP介导的。已证明FK506结合蛋白高度保守，即在所有测试的真核细胞中都存在，并在体外表现出肽基脯氨酰顺反异构酶（PPIase）活性。讨论了这些基因座的可能功能。除了对FK506的抗性外，未检测到其他突变表型，即使在缺乏NcFKBP以及亲环蛋白的双突变体中也是如此。亲环蛋白介导免疫抑制药物环孢菌素A的细胞毒性作用，并且在体外也具有PPIase活性。所研究的两个FK506抗性等位基因在强制异核体中均表现出不完全显性。提出了一种机制来解释这种显性，特别是考虑到NcFKBP缺陷等位基因fb。
