Cellular Protein Chemistry, Department of Chemistry, Utrecht University, Utrecht, The Netherlands.
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
Life Sci Alliance. 2019 Jan 18;2(1). doi: 10.26508/lsa.201800172. Print 2019 Feb.
Cystic fibrosis is caused by mutations in the gene, which are subdivided into six classes. Mutants of classes III and IV reach the cell surface but have limited function. Most class-III and class-IV mutants respond well to the recently approved potentiator VX-770, which opens the channel. We here revisited function and folding of some class-IV mutants and discovered that R347P is the only one that leads to major defects in folding. By this criterion and by its functional response to corrector drug VX-809, R347P qualifies also as a class-II mutation. Other class-IV mutants folded like wild-type CFTR and responded similarly to VX-809, demonstrating how function and folding are connected. Studies on both types of defects complement each other in understanding how compounds improve mutant CFTR function. This provides an attractive unbiased approach for characterizing mode of action of novel therapeutic compounds and helps address which drugs are efficacious for each cystic fibrosis disease variant.
囊性纤维化是由 基因突变引起的，这些突变可分为六类。III 类和 IV 类突变体到达细胞表面，但功能有限。大多数 III 类和 IV 类突变体对最近批准的增敏剂 VX-770 反应良好，该药物能打开通道。我们在这里重新研究了一些 IV 类突变体的功能和折叠，发现只有 R347P 会导致折叠的主要缺陷。根据这一标准和对校正药物 VX-809 的功能反应，R347P 也符合 II 类突变。其他 IV 类突变体的折叠方式与野生型 CFTR 相似，对 VX-809 的反应也相似，这表明了功能和折叠是如何相关联的。这两种类型缺陷的研究相互补充，有助于理解化合物如何改善突变 CFTR 的功能。这为表征新型治疗化合物的作用模式提供了一种有吸引力的无偏方法，并有助于确定哪些药物对每种囊性纤维化疾病变异有效。
