Wong Sharon L, Awatade Nikhil T, Astore Miro A, Allan Katelin M, Carnell Michael J, Slapetova Iveta, Chen Po-Chia, Capraro Alexander, Fawcett Laura K, Whan Renee M, Griffith Renate, Ooi Chee Y, Kuyucak Serdar, Jaffe Adam, Waters Shafagh A
School of Women's and Children's Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia.
Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), UNSW Sydney, Sydney, Australia.
iScience. 2021 Dec 31;25(1):103710. doi: 10.1016/j.isci.2021.103710. eCollection 2022 Jan 21.
Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R- mutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes.
对位于CFTR氯离子通道套索基序中的I37R突变进行了表征，方法是对来自增强剂和校正剂类别的几种CFTR调节剂进行分型。对I37R/F508del CFTR基因型个体的直肠活检中的肠道电流测量、肠道类器官中的福斯可林诱导肿胀（FIS）以及类器官衍生单层中的短路电流测量表明，I37R-CFTR导致残余功能缺陷，可通过增强剂和III型而非I型校正剂进行治疗。使用磷酸化、ATP结合的人CFTR扩展模型对I37R进行分子动力学研究，发现套索基序构象发生改变，这导致套索基序、调节（R）结构域和跨膜结构域2（TMD2）之间的相互作用出现不利增强。I37R突变的结构和功能表征增进了对CFTR通道调节的理解，并为扩大对超罕见基因型CF患者的药物可及性提供了一条潜在途径。
