ABCC7 p.Ser108Cys
| ClinVar: |
c.323C>T
,
p.Ser108Phe
?
, not provided
|
| CF databases: |
c.323C>T
,
p.Ser108Phe
(CFTR1)
D
, This mutation was identified by direct DNA sequencing with an automatic ABI 373A sequencer and is a single base substitution from C to T at position 455 of the CFTR gene. We have detected this mutation by SSCP analysis once in 25 non-[delta]F508 chromosomes. The patient is a 19 year old German young man. He carries a [delta]F508 mutation at his other CF chromosome.
|
| Predicted by SNAP2: | A: N (97%), C: N (87%), D: N (87%), E: N (82%), F: N (72%), G: N (93%), H: N (87%), I: N (72%), K: N (82%), L: N (78%), M: N (78%), N: N (97%), P: N (78%), Q: N (87%), R: N (78%), T: N (97%), V: N (82%), W: N (61%), Y: N (82%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: D, Q: N, R: D, T: N, V: D, W: N, Y: N, |
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[hide] Cysteine scanning of CFTR's first transmembrane se... Biophys J. 2013 Feb 19;104(4):786-97. doi: 10.1016/j.bpj.2012.12.048. Gao X, Bai Y, Hwang TC
Cysteine scanning of CFTR's first transmembrane segment reveals its plausible roles in gating and permeation.
Biophys J. 2013 Feb 19;104(4):786-97. doi: 10.1016/j.bpj.2012.12.048., [PMID:23442957]
Abstract [show]
Previous cysteine scanning studies of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have identified several transmembrane segments (TMs), including TM1, 3, 6, 9, and 12, as structural components of the pore. Some of these TMs such as TM6 and 12 may also be involved in gating conformational changes. However, recent results on TM1 seem puzzling in that the observed reactive pattern was quite different from those seen with TM6 and 12. In addition, whether TM1 also plays a role in gating motions remains largely unknown. Here, we investigated CFTR's TM1 by applying methanethiosulfonate (MTS) reagents from both cytoplasmic and extracellular sides of the membrane. Our experiments identified four positive positions, E92, K95, Q98, and L102, when the negatively charged MTSES was applied from the cytoplasmic side. Intriguingly, these four residues reside in the extracellular half of TM1 in previously defined CFTR topology; we thus extended our scanning to residues located extracellularly to L102. We found that cysteines introduced into positions 106, 107, and 109 indeed react with extracellularly applied MTS probes, but not to intracellularly applied reagents. Interestingly, whole-cell A107C-CFTR currents were very sensitive to changes of bath pH as if the introduced cysteine assumes an altered pKa-like T338C in TM6. These findings lead us to propose a revised topology for CFTR's TM1 that spans at least from E92 to Y109. Additionally, side-dependent modifications of these positions indicate a narrow region (L102-I106) that prevents MTS reagents from penetrating the pore, a picture similar to what has been reported for TM6. Moreover, modifications of K95C, Q98C, and L102C exhibit strong state dependency with negligible modification when the channel is closed, suggesting a significant rearrangement of TM1 during CFTR's gating cycle. The structural implications of these findings are discussed in light of the crystal structures of ABC transporters and homology models of CFTR.
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No. Sentence Comment
137 (B) The same protocol was adopted for S108C/Cysless mutant channels, which exhibit little response to external MTSES.
X
ABCC7 p.Ser108Cys 23442957:137:38
status: NEW