Correctors Enhance Maturation of ΔF508 CFTR by Promoting Interactions between the Two Halves of the Molecule
Bibliographic record
Abstract
Deletion of Phe508 in cystic fibrosis transmembrane conductance regulator (DeltaF508 CFTR) causes cystic fibrosis. CFTR consists of two homologous halves with each containing a nucleotide-binding domain (NBD) and a transmembrane domain (TMD). DeltaF508 CFTR appears to be trapped in an incompletely folded state. Small molecules (correctors) promote folding of DeltaF508 CFTR with relatively low efficiency. Understanding the mechanism of repair may lead to the development of more effective correctors. Here we tested the effect of correctors and the DeltaF508 mutation on interactions between the halves of CFTR when expressed as separate polypeptides. Glycosylation of C-half CFTR was defective when expressed alone as a mixture of core and unglycosylated proteins was detected. Coexpression of C-half CFTR with either wild-type N-half or DeltaF508/N-half CFTR, however, increased the amount of core-glycosylated protein, but only coexpression with wild-type N-half promoted maturation of C-half CFTR (Endo H resistant). This suggested that the DeltaF508 mutation inhibited some interactions between N-half and C-half CFTRs. Interaction of A52-tagged wild-type N-half or DeltaF508/N-half CFTR with histidine-tagged C-half CFTR was then followed by nickel-chelate chromatography. Coexpression of A52-tagged wild-type N-half or DeltaF508/N-half CFTR with histidine-tagged C-half CFTR resulted in the wild-type N-half CFTR but not DeltaF508/N-half CFTR protein being retained on the column. Coexpression of DeltaF508/N-half and C-half CFTR in the presence correctors VX-325 and corr-4a, however, restored interactions between the two halves. An interaction that was restored was that between NBD1 and TMD2 as the correctors restored cross-linking of mutant DeltaF508/NBD1(V510C)/TMD2(A1067C). Therefore, correctors promote proper interactions between the two halves of CFTR.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".