ABCC7 p.Gln207Cys
| ClinVar: |
c.619C>T
,
p.Gln207*
?
, not provided
|
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (85%), E: D (75%), F: D (85%), G: D (80%), H: D (85%), I: D (85%), K: D (85%), L: D (85%), M: D (75%), N: D (80%), P: D (91%), R: D (85%), S: D (71%), T: D (75%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Channel-lining residues in the M3 membrane-spannin... Biochemistry. 1998 Sep 1;37(35):12233-40. Akabas MH
Channel-lining residues in the M3 membrane-spanning segment of the cystic fibrosis transmembrane conductance regulator.
Biochemistry. 1998 Sep 1;37(35):12233-40., 1998-09-01 [PMID:9724537]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) forms a chloride-selective channel. Residues from the 12 putative membrane-spanning segments form at least part of the channel lining. We need to identify the channel-lining residues in order to understand the structural basis for the channel's functional properties. Using the substituted-cysteine-accessibility method we mutated to cysteine, one at a time, 24 consecutive residues (Asp192-Ile215) in the M3 membrane-spanning segment. Cysteines substituted for His199, Phe200, Trp202, Ile203, Pro205, Gln207, Leu211, and Leu214 reacted with charged, sulfhydryl-specific reagents that are derivatives of methanethiosulfonate (MTS). We infer that these residues are on the water-accessible surface of the protein and probably form a portion of the channel lining. When plotted on an alpha-helical wheel the exposed residues from Gln207 to Leu214 lie within an arc of 60 degrees; the exposed residues in the cytoplasmic half (His199-Ile203) lie within an arc of 160 degrees. We infer that the secondary structures of the extracellular and cytoplasmic halves of M3 are alpha-helical and that Pro205, in the middle of the M3 segment, may bend the M3 segment, moving the cytoplasmic end of the segment in toward the central axis of the channel. The bend in the M3 segment may help to narrow the channel lumen near the cytoplasmic end. In addition, unlike full-length CFTR, the current induced by the deletion construct, Delta259, is inhibited by the MTS reagents, implying that the channel structure of Delta259 is different than the channel structure of wild-type CFTR.
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No. Sentence Comment
113 In contrast, a 1-min application of 10 mM MTSES- significantly inhibited the CFTR-induced currents for the mutants H199C, F200C, W202C, I203C, P205C, Q207C, and L211C (Figure 4).
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ABCC7 p.Gln207Cys 9724537:113:150
status: NEW[hide] The cystic fibrosis V232D mutation inhibits CFTR m... Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9. Loo TW, Clarke DM
The cystic fibrosis V232D mutation inhibits CFTR maturation by disrupting a hydrophobic pocket rather than formation of aberrant interhelical hydrogen bonds.
Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9., [PMID:24412276]
Abstract [show]
Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis. Repair of CFTR mutants requires an understanding of the mechanisms of misfolding caused by processing mutations. Previous studies on helix-loop-helix fragments of the V232D processing mutation suggested that its mechanism was to lock transmembrane (TM) segments 3 and 4 together by a non-native hydrogen bond (Asp232(TM4)/Gln207(TM3)). Here, we performed mutational analysis to test for Asp232/Gln207 interactions in full-length CFTR. The rationale was that a V232N mutation should mimic V232D and a V232D/Q207A mutant should mature if the processing defect was caused by hydrogen bonds. We report that only Val232 mutations to charged amino acids severely blocked CFTR maturation. The V232N mutation did not mimic V232D as V232N showed 40% maturation compared to 2% for V232D. Mutation of Val232 to large nonpolar residues (Leu, Phe) had little effect. The Q207L mutation did not rescue V232D because Q207L showed about 50% maturation in the presence of corrector VX-809 while V232D/Q207A could no longer be rescued. These results suggest that V232D inhibits maturation by disrupting a hydrophobic pocket between TM segments rather than forming a non-native hydrogen bond. Disulfide cross-linking analysis of cysteines W356C(TM6) and W1145C(TM12) suggest that the V232D mutation inhibits maturation by trapping CFTR as a partially folded intermediate. Since correctors can efficiently rescue V232D CFTR, the results suggest that hydrophilic processing mutations facing a hydrophobic pocket are good candidates for rescue with pharmacological chaperones.
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None has been submitted yet.
No. Sentence Comment
99 Gln207 does not appear to be essential for activity since it was found that the Q207C CFTR mutant was active when expressed in frog oocytes [32].
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ABCC7 p.Gln207Cys 24412276:99:80
status: NEW100 The V232D, V232D/Q207A, V232D/Q207L, and V232D/Q207C mutants were then expressed in the presence or absence of corrector VX-809 to test for maturation.
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ABCC7 p.Gln207Cys 24412276:100:47
status: NEW104 By contrast, none of the Gln207 mutations rescued V232D CFTR (Fig. 1B and C) as no mature CFTR was observed when mutants V232D/Q207A, V232D/Q207L, or V232D/Q207C were expressed in the presence or absence of VX-809 (Fig. 1B).
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ABCC7 p.Gln207Cys 24412276:104:156
status: NEW107 Mutations to Gln207 inhibit CFTR maturation Since V232D but not mutants V232D/Q207A, V232D/Q207L, or V232D/Q207C could be rescued with VX-809 (Fig. 1B), we tested if maturation of CFTR was also sensitive to changes to Gln207 in a wild-type background.
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ABCC7 p.Gln207Cys 24412276:107:107
status: NEW117 the Q207A, Q207L or Q207C changes.
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ABCC7 p.Gln207Cys 24412276:117:20
status: NEW182 It was observed that in the absence of VX-809, the V510D mutation significantly improved the maturation of Q207L, Q207C, Q207E, Q207N and Q207S (Fig. 6A and B).
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ABCC7 p.Gln207Cys 24412276:182:114
status: NEW183 Mature CFTR was the major product in Q207N/V510D (90% mature product) while mutants Q207L/V510D, Q207C/V510D, Q207E/V510D, and Q207S/V510D showed modest levels of mature CFTR (about 20-40% mature).
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ABCC7 p.Gln207Cys 24412276:183:97
status: NEW184 In the presence of corrector VX-809 however, the amount of mature CFTR in mutants V510D/Q207A V510D/Q207L, V510D/Q207C, V510D/Q207E, V510D/Q207F and V510D/Q207S were significantly increased (25-85% mature product).
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ABCC7 p.Gln207Cys 24412276:184:113
status: NEW284 Although mutants such as A207A, Q207L and Q207C could be rescued with corrector VX-809 (Fig. 2), the V232D mutation appeared to have an effect that was independent of that of Gln207 since mutants Q207A/V232D, Q207L/V232D and Q207C/V232D could no longer be rescued by VX-809 (Fig. 1B).
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ABCC7 p.Gln207Cys 24412276:284:42
status: NEWX
ABCC7 p.Gln207Cys 24412276:284:225
status: NEW