Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation

Meng, Xianjun; Wang, Yiting; Wang, Xiaomeng; Wrennall, Joe A; Rimington, Tracy L.; Li, Hongyu; Cai, Zhiwei; Ford, Robert C.; Sheppard, David N.

doi:10.1074/jbc.m116.751537

Cited by 43 publications

(88 citation statements)

References 78 publications

(154 reference statements)

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“…The ∆F508 mutation also impairs CFTR assembly (58) partly because of abnormal domain‐domain interactions (14–16, 18). CFTR correctors and potentiators may rescue ∆F508‐CFTR defects by targeting some of these abnormalities (23, 25, 59).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, impaired domain‐domain interactions might accelerate ∆F508‐CFTR degradation by the peripheral protein quality control mechanism (5), decrease channel thermostability (23, 24), and reduce open probability ( P o ) (14, 16). Correcting individual structural defects (23, 25) seems to be a promising strategy to restore ∆F508‐CFTR function. However, it is unclear whether loss of function of the F508 residue could account for all abnormalities in ∆F508‐CFTR.…”

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confidence: 99%

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A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

et al. 2019

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People with the genetic disease cystic fibrosis (CF) often carry a deletion mutation ∆F508 on the gene encoding the CF transmembrane conductance regulator (CFTR) Cl− channel. This mutation greatly reduces the CFTR maturation process and slows the channel opening rate. Here, we investigate whether residues near F508 contribute to these defects in ∆F508‐CFTR. Most deletion mutations, but not alanine substitutions, of individual residues from positions 503 to 513 impaired CFTR maturation. Interestingly, only protein processing of ∆Y512‐CFTR, like that of ∆F508‐CFTR, was greatly improved by low‐temperature culture at 27°C or small‐molecule corrector C18. The 2 mutant Cl− channels were equally slow to open, suggesting that they may share common structural flaws. Studies on the H3‐H4 loop that links residues F508 and Y512 demonstrate that G509A/V510G mutations, moving G5091 position backward in the loop, markedly enhanced ∆F508‐CFTR maturation and opening rate while promoting protein stability and persistence of the H3 helix in ∆F508 nucleotide‐binding domain 1. Moreover, V510A/S511A mutations noticeably increased ∆Y512‐CFTR maturation at 27°C and its opening rate. Thus, loop abnormalities may contribute to ∆F508‐ and ∆Y512‐CFTR defects. Importantly, correcting defects from G509 displacement in ∆F508‐CFTR may offer a new avenue for drug discovery and CF treatments.—Chen, X., Zhu, S., Zhenin, M., Xu, W., Bose, S. J., Wong, M. P.‐F., Leung, G. P. H., Senderowitz, H., Chen, J.‐H. A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation. FASEB J. 33, 5126–5142 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

et al. 2019

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“…It is possible that this combination regiment can benefit patients carrying mutations other than ΔF508 since these two drugs act on two completely different steps for CFTR function. Lately, it was also shown that chronic co-treatment with Lumacaftor plus Ivacaftor restores stability of a small sub-population of ΔF508-CFTR Cl − channels with a majority of the mutants remaining destabilized [51]. A recent study showed that VX-770 acts additively with VX-809 to restore CFTR function in chronically treated R117H/ ΔF508 cells [52].…”

Section: Ongoing Challenges and Future Perspectivesmentioning

confidence: 99%

CFTR potentiators: from bench to bedside

Jih

Lin²,

Saito

et al. 2017

Current Opinion in Pharmacology

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One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease—dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features an energetic coupling between NBD dimerization and gate opening/closing in CFTR’s TMDs. Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs. This latter idea also explains the near omnipotence of Ivacaftor. Furthermore, this model marks multiple approaches to synergistically boost the open probability of CFTR by influencing distinct molecular events that control gating conformational changes.

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“…Biochemical and biophysical studies suggest that VX‐809 and VX‐770 interact directly with the hCFTR protein . Molecular docking studies and mutagenesis studies have implicated potential binding sites for VX‐809, yet uncertainty remains, as no direct binding assays have yet been developed.…”

Section: Introductionmentioning

confidence: 99%

Activity of lumacaftor is not conserved in zebrafish Cftr bearing the major cystic fibrosis‐causing mutation

Laselva

Erwood

et al. 2019

FASEB BioAdvances

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F508del‐cystic fibrosis transmembrane conductance regulator (CFTR) is the major mutant responsible for cystic fibrosis (CF). ORKAMBI®, approved for patients bearing this mutant, contains lumacaftor (VX‐809) that partially corrects F508del‐CFTR's processing defect and ivacaftor (VX‐770) that potentiates its defective channel activity. Unfortunately, the clinical efficacy of ORKAMBI® is modest, highlighting the need to understand how the small molecules work so that superior compounds can be developed. Because, human CFTR (hCFTR) and zebrafish Cftr (zCftr) are structurally conserved as determined in recent cryo‐EM structural models, we hypothesized that the consequences of the major mutation and small molecule modulators would be similar for the two species of protein. As expected, like the F508del mutation in hCFTR, the homologous mutation in zCftr (F507del) is misprocessed, yet not as severely as the human mutant and this defect was restored by low‐temperature (27°C) culture conditions. After rescue to the cell surface, F507del‐zCftr exhibited regulated channel activity that was potentiated by ivacaftor. Surprisingly, lumacaftor failed to rescue misprocessing of the F507del‐zCftr at either 37 or 27°C suggesting that future comparative studies with F508del‐hCFTR would provide insight into its structure: function relationships. Interestingly, the robust rescue of F508del‐zCftr at 27°C and availability of methods for in vivo screening in zebrafish present the opportunity to define the cellular pathways underlying rescue.

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Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation

Cited by 43 publications

References 78 publications

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

CFTR potentiators: from bench to bedside

Activity of lumacaftor is not conserved in zebrafish Cftr bearing the major cystic fibrosis‐causing mutation

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