Conformational and Temperature-sensitive Stability Defects of the ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator in Post-endoplasmic Reticulum Compartments

Sharma, Manu; Benharouga, Mohamed; Hu, Wei; Lukacs, Gergely L.

doi:10.1074/jbc.m009172200

Cited by 204 publications

(228 citation statements)

References 46 publications

Supporting

Mentioning

213

Contrasting

Order By: Relevance

“…However, it remains possible that deletion of F508 causes intrinsic misfolding and͞or structural instability of NBD1 at steady state (39,40). Supporting this idea, the F508del-CFTR Cl Ϫ channel has a gating defect characterized by a reduction in the duration of channel openings and a dramatic prolongation of periods when the channel is closed.…”

Section: Rk and G550e Rescue F508del-cftr Channel Gating With Differentmentioning

confidence: 66%

Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms

Roxo-Rosa

Schmidt

et al. 2006

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

106

131

View full text Add to dashboard Cite

The revertant mutations G550E and 4RK [the simultaneous mutation of four arginine-framed tripeptides (AFTs): R29K, R516K, R555K, and R766K] rescue the cell surface expression and function of F508del-cystic fibrosis (CF) transmembrane conductance regulator (-CFTR), the most common CF mutation. Here, we investigate their mechanism of action by using biochemical and functional assays to examine their effects on F508del and three CF mutations (R560T, A561E, and V562I) located within a conserved region of the first nucleotide-binding domain (NBD1) of CFTR. Like F508del, R560T and A561E disrupt CFTR trafficking. G550E rescued the trafficking defect of A561E but not that of R560T. Of note, the processing and function of V562I were equivalent to that of wild-type (wt)-CFTR, suggesting that V562I is not a disease-causing mutation. Biochemical studies revealed that 4RK generates higher steady-state levels of mature CFTR (band C) for wtand V562I-CFTR than does G550E. Moreover, functional studies showed that the revertants rescue the gating defect of F508del-CFTR with different efficacies. 4RK modestly increased F508del-CFTR activity by prolonging channel openings, whereas G550E restored F508del-CFTR activity to wt levels by altering the duration of channel openings and closings. Thus, our data suggest that the revertants G550E and 4RK might rescue F508del-CFTR by distinct mechanisms. G550E likely alters the conformation of NBD1, whereas 4RK allows F508del-CFTR to escape endoplasmic reticulum retention͞retrieval mediated by AFTs. We propose that AFTs might constitute a checkpoint for endoplasmic reticulum quality control. endoplasmic reticulum quality control ͉ folding ͉ membrane traffic ͉ arginine-framed motifs ͉ trafficking signals

show abstract

Section: Rk and G550e Rescue F508del-cftr Channel Gating With Differentmentioning

confidence: 66%

Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms

Roxo-Rosa

Schmidt

et al. 2006

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

106

131

View full text Add to dashboard Cite

show abstract

“…The chemical chaperone 4-phenylbutyric acid mediated a marked increase in secretion of ␣ 1 -antitrypsin (49). Recent studies, however, suggest that the rescued protein is less stable than the WT (47). Other approaches to inducing the folding of proteins have been developed.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

View full text Add to dashboard Cite

Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

show abstract

“…Interestingly, there is still a slight remaining CFTR function in CF patients being homozygous for p.Phe508del, indicating that some CFTR proteins pass the ER quality control and reach the apical membrane. 46 We think that variants in direct interacters like PP2A and SNAP23 might enhance the residual function of CFTR while variants in KRT19, which are involved in trafficking of CFTR, might raise the amount of functional CFTR at the apical membrane and therefore modify CF disease.…”

Section: Discussionmentioning

confidence: 97%

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

et al. 2012

View full text Add to dashboard Cite

There is growing evidence that the great phenotypic variability in patients with cystic fibrosis (CF) not only depends on the genotype, but apart from a combination of environmental and stochastic factors predominantly also on modifier gene effects. It has been proposed that genes interacting with CF transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed the impact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CF disease outcome. SNPs that potentially alter gene function were genotyped in 95 well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysis was used to assess the relationship between sequence variants and the repeated measurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes. Twenty-five SNPs were used for statistical analysis, where we found strong associations for one SNP in PPP2R4 with the lung clearance index (Pr0.01), the specific effective airway resistance (Pr0.005) and the forced expiratory volume in 1 s (Pr0.005). In addition, we identified one SNP in SNAP23 to be significantly associated with three lung function parameters as well as one SNP in PPP2R1A and three in KRT19 to show a significant influence on one lung function parameter each. Our findings indicate that direct interacters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residual function of p.Phe508del-CFTR while variants in KRT19 may modulate the amount of p.Phe508del-CFTR at the apical membrane and consequently modify CF disease.

show abstract

Conformational and Temperature-sensitive Stability Defects of the ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator in Post-endoplasmic Reticulum Compartments

Cited by 204 publications

References 46 publications

Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms

Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

Contact Info

Product

Resources

About