The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue

Joshi, Deepak; Simhaev, Luba; Oliver, Kathryn E.; Senderowitz, Hanoch; Willigen, Marcel van; Braakman, Ineke; Rab, András; Sorscher, Eric J.; Hong, Jeong S.

doi:10.1016/j.jbc.2021.100598

Cited by 28 publications

(34 citation statements)

References 84 publications

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“…One key feature of allostery may be linked to the shift of the lasso Lh2 upon VX-809 binding and the associated interaction of D47 with K162, allowing a synergy between three communication pathways leading from MSD1 to K162 (the TM2 way: M152 K162; two elbow-Lh2 ways: (i) R74 R75 E56 D47 K162, (ii) R74 R75 E56 E54 K163 K162) (Table S1). The critical role played by this pivotal interface in CFTR assembly and pharmacological repair, is also highlighted by other recent studies focused on ICL1 and Lh2 [8,73,74]. These results presented here in the F508del background indicate the necessity of stabilizing inter-domain folding steps to efficiently rescue misfolded F508del, contrary to L206W (Fig.…”

Section: Discussionsupporting

confidence: 79%

Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR

Baatallah

Elbahnsi

Mornon

et al. 2021

Cell. Mol. Life Sci.

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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Section: Discussionsupporting

confidence: 79%

Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR

Baatallah

Elbahnsi

Mornon

et al. 2021

Cell. Mol. Life Sci.

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“…These results confirm the mechanistic classification of the correctors as proposed earlier [ 19 , 20 , 27 ] and show that mutations, which are highly responsive to stabilization of the MSD1 and MSD1-NBD1, can be further corrected by correctors targeting the NBD1 or NBD2. This is in agreement with a recent study reporting that P67L impairs folding of downstream domains including the NBD1 and NBD2 [ 44 ].…”

Section: Resultssupporting

confidence: 94%

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Veit

Velkov

et al. 2021

JPM

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Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

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“…These structures have provided insights into the molecular mechanisms of CFTR channel function, i.e., its anion conductance pathway [ 35 ], as well as identified new features not previously described in ABC transporters, such as the N-terminal lasso motif [ 32 ]. This motif is of importance for CFTR channel gating as well as for folding of downstream domains and thereby might (partially) explain the molecular mechanism of several missense mutations located within this motif or in its vicinity [ 36 , 37 , 38 ]. Cryo-EM was further also used to determine the binding site of CFTR corrector VX-809 ( see Section 3.2.1 .…”

Section: One Size Does Not Fit Allmentioning

confidence: 99%

One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

Ensinck

Carlon

2022

Cells

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Cystic fibrosis (CF) is the most common monogenic disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Over the last 30 years, tremendous progress has been made in understanding the molecular basis of CF and the development of treatments that target the underlying defects in CF. Currently, a highly effective CFTR modulator treatment (Kalydeco™/Trikafta™) is available for 90% of people with CF. In this review, we will give an extensive overview of past and ongoing efforts in the development of therapies targeting the molecular defects in CF. We will discuss strategies targeting the CFTR protein (i.e., CFTR modulators such as correctors and potentiators), its cellular environment (i.e., proteostasis modulation, stabilization at the plasma membrane), the CFTR mRNA (i.e., amplifiers, nonsense mediated mRNA decay suppressors, translational readthrough inducing drugs) or the CFTR gene (gene therapies). Finally, we will focus on how these efforts can be applied to the 15% of people with CF for whom no causal therapy is available yet.

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The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue

Cited by 28 publications

References 84 publications

Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR

Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

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