Multiple proteolytic systems, including the proteasome, contribute to CFTR processing
Perturbation of Hsp90 interaction with nascent CFTR prevents its maturation and accelerates its degradation by the proteasome
This work shows the first direct evidence of a role for Hsp90 in the maturation of a newly synthesized integral membrane protein by interaction with its cytoplasmic domains on the ER surface.
Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR)
Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta F508 CFTR present in most patients with cystic fibrosis.
Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein
It is shown that several compounds identified by high‐throughput screening to improve ΔF508 CFTR maturation, including the investigational drug VX‐809, caused a much greater increase in maturation at 27 than at 37°C (<2‐fold), and it is clearly demonstrate that ΔF504 CFTR can be completely assembled and evade cellular quality control systems, while remaining thermally unstable.
Regulatory insertion removal restores maturation, stability and function of DeltaF508 CFTR.
Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR.
Restoration of domain folding and interdomain assembly by second‐site suppressors of the ΔF508 mutation in CFTR
- Lihua He, L. Aleksandrov, Liying Cui, T. Jensen, Kenneth L. Nesbitt, J. Riordan
- BiologyThe FASEB Journal
- 1 August 2010
It is found that the suppressors restored maturation of only those processing mutations located in NBD1, but not in other domains, including those in the C‐terminal cytoplasmic loop of the second membrane‐spanning domain, which forms an interface with the NBD 1 surface.
Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance
Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator
It is found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and ΔF508 from the ER to the plasma membrane, and the absence of N-linked oligosaccharides did reduce the stability ofWild-type CFTR, causing significantly more-rapid turnover in post-ER compartments.