ABCC7 p.Ala274Cys
| Predicted by SNAP2: | C: N (66%), D: D (85%), E: D (71%), F: D (63%), G: D (71%), H: D (85%), I: N (66%), K: D (71%), L: N (78%), M: N (72%), N: D (75%), P: D (71%), Q: D (59%), R: D (85%), S: N (72%), T: N (61%), V: N (82%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | C: N, D: D, E: N, F: N, G: D, H: N, I: N, K: N, L: N, M: N, N: D, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] A small-molecule modulator interacts directly with... Mol Pharmacol. 2009 Jun;75(6):1430-8. Epub 2009 Apr 1. Wellhauser L, Kim Chiaw P, Pasyk S, Li C, Ramjeesingh M, Bear CE
A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability.
Mol Pharmacol. 2009 Jun;75(6):1430-8. Epub 2009 Apr 1., [PMID:19339490]
Abstract [show]
The deletion of Phe-508 (DeltaPhe508) constitutes the most prevalent of a number of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that cause cystic fibrosis (CF). This mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The biosynthetic defect can be partially overcome by small-molecule "correctors"; once at the cell surface, small-molecule "potentiators" enhance the channel activity of DeltaPhe508-CFTR. Certain compounds, such as VRT-532, exhibit both corrector and potentiator functions. In the current studies, we confirmed that the inherent chloride channel activity of DeltaPhe508-CFTR (after biosynthetic rescue) is potentiated in studies of intact cells and membrane vesicles. It is noteworthy that we showed that the ATPase activity of the purified and reconstituted mutant protein is directly modulated by binding of VRT-532 [4-methyl-2-(5-phenyl-1H-pyrazol-3-yl)-phenol] ATP turnover by reconstituted DeltaPhe508-CFTR is decreased by VRT-532 treatment, an effect that may account for the increase in channel open time induced by this compound. To determine whether the modification of DeltaPhe508-CFTR function caused by direct VRT-532 binding is associated with structural changes, we evaluated the effect of VRT-532 binding on the protease susceptibility of the major mutant. We found that binding of VRT-532 to DeltaPhe508-CFTR led to a minor but significant decrease in the trypsin susceptibility of the full-length mutant protein and a fragment encompassing the second half of the protein. These findings suggest that direct binding of this small molecule induces and/or stabilizes a structure that promotes the channel open state and may underlie its efficacy as a corrector of DeltaPhe508-CFTR.
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223 Loo et al. (2008) also found that deletion of Phe508 disrupted the chemical cross-linking that normally occurred between non-native cysteines of MSD1 (A274C) and NBD2 (Loo et al., 2008) and cross-linking between non-native cysteines introduced into transmembrane helices 6 (MSD1) and 7 or 12 (MSD2) (Wang et al., 2007).
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ABCC7 p.Ala274Cys 19339490:223:151
status: NEW