Bibliographic record
Abstract
Cytoplasmic portions of membrane proteins often contain disordered regions that can function as regulatory components.CFTR, the membrane protein chloride channel mutated in cystic fibrosis, is a dynamic biological machine that undergoes functional conformational changes.A significant modulator of this dynamic behavior is the ~200 residue cytoplasmic regulatory (R) region of CFTR, which is intrinsically disordered in isolation and which makes highly dynamic interactions with the nucleotide binding domains (NBDs) of CFTR, other segments of CFTR and other proteins.Similar to many other disordered proteins, the R region is a "hub" for regulatory protein interactions and is a site of regulatory phosphorylation, in this case by PKA, PKC and AMPK.Building on our previous work, we have performed NMR and fluorescence binding studies on non-phosphorylated and highly PKA phosphorylated states of the isolated R region and have demonstrated binding of the R region with NBD1, NBD2, and a 40-residue peptide from the C-terminus of CFTR, as well as the STAS domain of the SLC26A3 chloride-bicarbonate exchanger that is a co-regulator of CFTR, and the 14-3-3beta protein implicated in CFTR processing.Analysis of NMR resonance broadening and chemical shift changes upon binding coupled with fluorescence binding measurements provides evidence for multi-site interactions of various segments of the R region.Our interpretation of the binding to the NBDs is that the multiple elements interact by transiently stabilizing helical structure, while binding to the 14-3-3beta likely involves transient stabilization of extended structure around each of the PKA sites.The NBD binding is much stronger for the non-phosphorylated R region while binding to the C-terminus and 14-3-3beta is stronger for the PKA phosphorylated state.Initial studies of isolated peptides of the R region suggest that binding of the entire disordered "domain" provides enhancement with synergistic effects of these various interacting elements.The diversity of structural modes and electrostatic contributions to binding contribute to the complex regulatory mechanisms at play within CFTR.These studies provide more evidence for our proposed model of the R region as a highly dynamic integrator of different regulatory inputs in controlling both CFTR chloride channel gating and protein processing.As our understanding of the complexity of regulatory dynamics within CFTR develops, so will our understanding of their functional and pathological implications.This work was supported by the CF
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.745 | 0.521 |
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; the direct Gemma label and the distilled Codex classifier agree on what is shown here.
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".