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

Baatallah, Nesrine; Elbahnsi, Ahmad; Mornon, Jean‐Paul; Chevalier, B.; Pranke, Iwona; Servel, Nathalie; Zelli, Renaud; Décout, Jean‐Luc; Edelman, Aleksander; Sermet‐Gaudelus, Isabelle; Callebaut, Isabelle; Hinzpeter, Alexandre

doi:10.1007/s00018-021-03994-5

Cited by 40 publications

(79 citation statements)

References 77 publications

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“…Possibly the pocket created by the change of a Histidine to a Proline is different from that created by the deletion of Phe-508—thus explaining why VX-661 does not rescue H1079P-CFTR. However, the interdomain contacts may still create the putative NBD1 binding site of VX-445, for which the His-620 residue seems to be critical [ 43 ]. A similar rationale can be used for Q1100P, which is located in the middle of TM11, possibly influencing structure of ICL4, located in its vicinity, and thus also the NBD1-ICL4 interaction.…”

Section: Discussionmentioning

confidence: 99%

Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Ramalho

Silva

Amaral

et al. 2021

IJMS

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Most of the ~2100 CFTR variants so far reported are very rare and still uncharacterized regarding their cystic fibrosis (CF) disease liability. Since some may respond to currently approved modulators, characterizing their defect and response to these drugs is essential. Here we aimed characterizing the defect associated with four rare missense (likely Class II) CFTR variants and assess their rescue by corrector drugs. We produced CFBE cell lines stably expressing CFTR with W57G, R560S, H1079P and Q1100P, assessed their effect upon CFTR expression and maturation and their rescue by VX-661/VX-445 correctors. Results were validated by forskolin-induced swelling assay (FIS) using intestinal organoids from individuals bearing these variants. Finally, knock-down (KD) of genes previously shown to rescue F508del-CFTR was assessed on these mutants. Results show that all the variants preclude the production of mature CFTR, confirming them as Class II mutations. None of the variants responded to VX-661 but the combination rescued H1079P- and Q1100P-CFTR. The KD of factors that correct F508del-CFTR retention only marginally rescued R560S- and H1079P-CFTR. Overall, data evidence that Class II mutations induce distinct molecular defects that are neither rescued by the same corrector compounds nor recognized by the same cellular machinery, thus requiring personalized drug discovery initiatives.

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Section: Discussionmentioning

confidence: 99%

Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Ramalho

Silva

Amaral

et al. 2021

IJMS

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“…Although the binding sites for the different modulators are not completely clear, evidence has accumulated on the most probable locations. VX-809 has been suggested to bind to a TMD1 groove [162] and to a binding site at NBD1, promoting allosteric coupling to the intracellular loop 4/NBD1 interface that is directly affected by F508del [159,[163][164][165]. Modulator VX-661 has been proposed to target the same CFTR interaction.…”

Section: Interaction Profiles Of Rare Cftr Mutationsmentioning

confidence: 99%

“…Modulator VX-661 has been proposed to target the same CFTR interaction. There is much less data on the novel modulator VX-445, which was suggested to bind a site at NBD1 [166], which would involve a close contact with residue H620 [165]. VX-770 has been proposed to bind to two potential binding sites at the interface of the TMD1 and TMD2 of CFTR [167].…”

Section: Interaction Profiles Of Rare Cftr Mutationsmentioning

confidence: 99%

Revisiting CFTR Interactions: Old Partners and New Players

Farinha

Gentzsch

2021

IJMS

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Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

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“…It is aimed to change local environment temporarily as favorable for wound healing. Pharmacologic chaperone is a small organic chemical and can change protein folding as desirable direction [ 3 ]. The application of pharmacologic chaperone can be considered for challenging cases of unhealed wound caused by some systemic diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Chaperone produced by micro-organism is a kind of alarming signal to neighbors for helping successful transformation to dormancy [ 5 ]. Chaperone can bind to protein and changes protein conformation [ 3 , 5 ]. Chaperone-protein complex generally stabilizes protein conformation and this complex is more resistant to environmental stress [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

Kim

2022

Maxillofac Plast Reconstr Surg

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Abstract4-Hexylresorcinol (4HR) is amphiphilic organic chemical and auto-regulator for micro-organism. As 4HR administration induces the stress on the endoplasmic reticulum, 4HR changes protein folding. The application of 4HR inhibits NF-κB signal pathway and TNF-α production. In addition, 4HR administration increases VEGF, TGF-β1, and calcification associated proteins. As a consequence, 4HR administration increases angiogenesis and bone formation in wounded area. Strong anti-inflammatory reaction and capillary regeneration in diabetic model demonstrate that 4HR can be applied on many types of surgical wound.

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

Cited by 40 publications

References 77 publications

Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Revisiting CFTR Interactions: Old Partners and New Players

4-Hexylresorcinol: pharmacologic chaperone and its application for wound healing

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