CFTR Regulation by Phosphorylation
Bibliographic record
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a tightly regulated anion channel expressed in epithelial and other cells. It conducts chloride and bicarbonate ions through the plasma membrane and also influences the activity of other channels and transporters through unknown mechanisms. CFTR has two membrane domains (TM1, TM2), each comprised of six trans-membrane segments, two nucleotide-binding folds (NBD1, NBD2) that bind and hydrolyze ATP, and a central regulatory or “R” domain (). Phosphorylation of the R domain by protein kinases Table 1) stimulates channel activity and may also enhance interactions of CFTR with other proteins. This chapter describes methods that we have found useful for studying the phosphorylation and dephosphorylation of CFTR. We emphasize simple approaches for the partial purification of CFTR and for assaying kinase and phosphatase activities using either CFTR or casein as substrate. Table 1 Predicted Phosphorylation Sites in the R Domain for Protein Kinase A (PKA), Protein Kinase C (PKC), and Casein Kinase 2 (CK2) A Context Serines Pos ??↓ Score Pred Kinase 631 ---SELQN 0.002 . 641 QPDFSSKLM 0.390 . 642 PDFSSKLMG 0.015 . 649 MGCDSFDQF 0.007 . 654 FDQFSAERR 0.590 *S* 660 ERRNSILTE 0.981 *S* PKA 670 LHRFSLEGD 0.997 *S* PKA 678 DAPVSWTET 0.997 *S* CK2 686 TKKQSFKQT 0.986 *S* PKA/PKC 700 KRKNSILNP 0.958 *S* PKA 707 NPINSIRKF 0.096 . PKC 712 IRKFSIVQK 0.889 *S* PKA 728 IEEDSDEPL 0.985 *S* 737 ERRLSLVPD 0.988 *S* PKA 742 LVPDSEQGE 0.783 *S* 753 LPRISVIST 0.990 *S* PKA 756 ISVISTGPT 0.927 *S* 768 RRRQSVLNL 0.990 *S* PKA 776 LMTHSVNQG 0.009 . 790 KTTA STRKV 0.892 *S* PKC 795 TRKVSLAPQ 0.954 *S* PKA 809 LDIYSRRLS 0.023 . 813 SRRLSQETG 0.997 *S* PKA B Context Threonines Pos ↓ Score Pred 663 NSILTETLH 0.064 . 665 ILTETLHRF 0.235 . 680 PVSWTETKK 0.055 . 682 SWTETKKQS 0.903 *T* PKC 690 SFKQTGEFG 0.068 . 717 IVQKTPLQM 0.122 . 757 SVISTGPTL 0.023 . 760 STGPTLQAR 0.033 . 774 LNLMTHSVN 0.024 . 787 IHRKTTAST 0.814 *T* PKA 788 HRKTTASTR 0.498 . 791 TTASTRKVS 0.760 *T* PKC QANLTELDI 0.021 . 816 LSQETGLEI 0.050 . C Tyrosines Pos Context Score Pred 808 ELDIYSRRL 0.474 . Score indicates probability the site would be phosphorylated according to NetPhos 2.0, a program that uses experimentally observed phosphoryla- tions in a large protein database.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.004 |
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".