The Primary Folding Defect and Rescue of ΔF508 CFTR Emerge during Translation of the Mutant Domain

Hoelen, Hanneke; Kleizen, Bertrand; Schmidt, André; Richardson, John P.; Charitou, Paraskevi; Thomas, Philip; Braakman, Ineke

doi:10.1371/journal.pone.0015458

Cited by 79 publications

(173 citation statements)

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“…In CFTR, specific residues in the ABC signature sequence were found to be critical for NBD stability, and introduction of secondary suppressor mutations into the signature sequence could rescue the ΔF508 protein expression and specifically the stability of the isolated NBD1 domain (20,21,(29)(30)(31). To test whether or not Q141K decreases stability of the ABCG2 NBD, we introduced stabilizing mutations into the signature sequence to try to rescue protein expression.…”

Section: Resultsmentioning

confidence: 99%

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Woodward

Tukaye

Cui

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

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ABCG2 is a secretory efflux uric acid transporter of the kidney proximal tubule and gut that plays a key role in uric acid excretion. Genetic defect in ABCG2 leads to significant increases in serum urate levels (SUA) causing hyperuricemia and gout. A single common variant, Q141K, is responsible for the majority of ABCG2 associated gout risk. The Q141K mutation is a loss of function mutation associated with a severe reduction in protein abundance and transport function. Previously we hypothesized the Q141K mutation leads to instability in the nucleotide‐binding domain and here we present the specific molecular mechanism of the defect and a proof of concept of its correction using small molecules. We found using a ABCG2 structural model and targeted amino acid substitutions that the Q141K mutations leads to a localized disruption in packing that affects abundance and can be partially rescued with a secondary substitution at H155A. However the use of the signature motif suppressor mutation, G188E, provides full rescue of the Q141K abundance by stabilizing the NBD dimer sandwich, a finding consistent with a Q141K defect in NBD dimer formation. Finally we show that a small molecule, VRT‐325, known to bind directly to the NBD of ABC transporters can rescue both abundance and function of Q141K ABCG2.

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Section: Resultsmentioning

confidence: 99%

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Woodward

Tukaye

Cui

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

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“…The gene causing the disease is localized on the 7th chromosome. The spread mutation detected in CF is ΔF508 and over 1500 mutations have been determined (2,3) . Several hundreds of cystic fibrosis transmembrane conductance regulator (CFTR) variants have been reported, it is not known whether they are causing CF or not.…”

Section: ıNtroductıonmentioning

confidence: 99%

“…M470 and the combined V frequency are seen in the subSaharan Africa. Although there was polymorphism, M470V may cause clinical issues, such as congenital bilateral absence of the vas deferens in Chinese males (2,4,5) .…”

Section: ıNtroductıonmentioning

confidence: 99%

The Importance of the M470V Polymorphism

Çelik¹,

Güneşaçar²,

Balcı³

et al. 2017

BUCH

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Objective: Several hundreds of cystic fibrosis transmembrane conductance regulator (CFTR) variants have been reported, however it is not known whether which one of them was causing the disease of cystic fibrosis (CF) or not. Information about CFTR genes carrying the M470 or the V470 allele are interesting. In this study, we aimed to investigate the clinical importance of M470V mutation in Antiochia region. Methods: A case-control study consisted of 145 children from whom CF gene study was requested because of recurrent respiratory tract infections, growth failure, chronic diarrhea and constipation. The parameters of patients with positive mutation were compared with negative ones as for gender, age, height, weight, annual number of upper and lower respiratory tract infections, parental consanguinity, sibling death, clinical and laboratory parametres. Results: In 63 of 145 patients (43.4%), heterozygous mutation, in 16 (11%) of them homozygous mutation was detected. All of the patients with mutation group had M470V mutation. The sweat test results of all patients were within normal limits. Mean age of those patients were 41.21±39.8 (min: 6 max: 192) months and 30 (38%) of them were girls. Thirty percent of the patients with mutation (n=17.7) had a familial history of cystic fibrosis, 2 a history of sibling death . In the mutation group, only annual number of infections, skin dryness, loss of weight, level of IgG and IgM were significantly higher (p<0.05). Conclusion: It was concluded that in M470V positive cases, the disease may cause clinical symptoms without affecting sweat test results, with less gastrointestinal but more respiratory symptoms, causing a more prominent loss of weight.

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“…1). The F508-induced misfolding of CFTR starts during translation immediately after the NBD1 emerges from the ribosome (Hoelen et al, 2010). This conformational defect originates in NBD1 but spread throughout the whole molecule through domain-domain interactions, leading to a global conformation defect (Du et al, 2005;Du & Lukacs, 2009;Roy et al, 2010).…”

Section: Cftr De Novo Folding In the Ermentioning

confidence: 99%

“…Restoring wild-type-like global conformation is required for F508 CFTR to pass the quality control and egress from the ER (Roy et al, 2010). Second site mutations in NBD1 have been identified that suppress the F508 processing defect (Teem et al, 1993), and at least some of such suppressing mutations can act co-translationally on the NBD1 misfolding (Hoelen et al, 2010). Therefore, the de novo folding of F508 CFTR at both cotranslational and post-translational levels can be targeted for its rescue.…”

Section: Cftr De Novo Folding In the Ermentioning

confidence: 99%

Improving Cell Surface Functional Expression of F508 CFTR: A Quest for Therapeutic Targets

Fan¹,

Banasavadi-Siddegowda²,

Wang³

2012

Cystic Fibrosis - Renewed Hopes Through Research

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The Primary Folding Defect and Rescue of ΔF508 CFTR Emerge during Translation of the Mutant Domain

Cited by 79 publications

References 50 publications

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

Gout-causing Q141K mutation in ABCG2 leads to instability of the nucleotide-binding domain and can be corrected with small molecules

The Importance of the M470V Polymorphism

Improving Cell Surface Functional Expression of F508 CFTR: A Quest for Therapeutic Targets

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