Fig. 1: Posttranslational rescue of ΔF508- and L206W-CFTR misfolding by VX-445 and VX-809 pharmacological chaperones. | Nature Communications

Fig. 1: Posttranslational rescue of ΔF508- and L206W-CFTR misfolding by VX-445 and VX-809 pharmacological chaperones.

From: Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling

Fig. 1: Posttranslational rescue of ΔF508- and L206W-CFTR misfolding by VX-445 and VX-809 pharmacological chaperones.The alternative text for this image may have been generated using AI.

a Left panel: The inward-facing human CFTR cryo-EM structure (PDB:5UAK). The same color-coding of CFTR domains (NBD1, NBD2, TMD1, and TMD2) is used for all relevant illustrations of MRP1 and ABCC6. P67, L206, and F508 residues were highlighted as spheres. Right panel: Interdomain contacts of CFTR. CL1,4 and CL2,3 form domain interfaces with NBD1 and NBD2, respectively. TMH1-6 and 7–12 are colored with blue-green and red-yellow gradients, respectively. b Conformational maturation efficiency of radioactively pulse-labeled L206W-CFTR in the absence or presence of VX-809 in BHK-21 cells. Cells were exposed to 3 μM VX-809 during depletion, pulse, and chase periods as indicated. B-band and C-band are the core- and complex-glycosylated CFTR, respectively. Phosphorimage visualization (left panel) and quantification of the maturation efficiency (right panel). Means ± S.E.M, n = 6 and 8. c Conformational maturation efficiency of ΔF508- and WT-CFTR was measured by radioactive pulse-chase technique and phosphorimage analysis in BHK-21 cells. Exposure to VX-445 (2 μM) and VX-809 (3 μM) during the Met/Cys depletion, pulse-labeling and/or chase is indicated by “+” in the corresponding rows. Pulse-labeling was also included without the chase (indicated by a gray box in “chase” row) to determine the total radioactivity incorporated into the core-glycosylated CFTR in the absence or presence of correctors. Means ± S.E.M, n = 7,3,6,3,5 from left to right. d Conformational maturation efficiency of the core-glycosylated L206W-CFTR into complex-glycosylated was measured as described in c. Cells were exposed to 3 μM VX-809 during depletion, pulse-labeling and/or chase as indicated by +. The gray box indicates that only pulse-labeling was included without the chase. Means ± S.E.M, n = 9, 4, 3, 3, 3, 3. In all figures P < 0.05 (*); < 0.01 (**); < 0.005 (***); < 0.0001 (****). Unpaired two-tailed t-test. Source data, including specific P values are provided as a Source Data file.

Back to article page