ABCMdb

ABCC7 p.Phe374Ala

Predicted by SNAP2:	A: D (66%), C: D (59%), D: D (91%), E: D (85%), G: D (85%), H: D (80%), I: D (63%), K: D (85%), L: D (71%), M: D (66%), N: D (85%), P: D (91%), Q: D (80%), R: D (85%), S: D (80%), T: D (80%), V: D (66%), W: D (80%), Y: N (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: N,

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Publications
[hide] VX-809 corrects folding defects in cystic fibrosis... Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7. Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, Cyr DM
VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.
Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7., [PMID:23924900]

Abstract [show]
Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

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No. Sentence Comment
72 Despite the severe biogenic defects exhibited by F374A-CFTR, L375A-CFTR, the double mutation F374A/L375A-CFTR (Figure 3A), F374A-CFTR 380, and L375A-CFTR 380 (Figure 3B), VX-809 almost completely suppressed the biogenic defects caused by the F374A and L375A mutations at the 5-bc;M concentration that maximally suppressed folding defects in F508del-CFTR (Figure 3, A and B). Login to comment
96 Interestingly, the positive effect of S2 and S3 on F508del-CFTR biogenesis was abolished by the F374A mutation, as VX-809 could not drive high-level accumulation of the folded C-band of F374A/S2/F508del-CFTR or F374A/S3/F508del-CFTR. Login to comment
97 In addition, the F374A mutation hindered VX-809 from suppressing folding defects in F508del-CFTR. Login to comment
98 In experiments with CFTR, the S2 and S3 mutations by themselves increased C-band accumulation almost twofold, and this effect was blocked by F374A (Figure 5C). Login to comment
99 Yet, in contrast to results with F508del-CFTR, VX-809 restored accumulation of the C-form of F374A/S2-CFTR and F374A/S3-CFTR to levels of S2 CFTR and S3 CFTR under control conditions. Login to comment
104 The folding defect caused by F374A is efficaciously corrected by VX-809 (Figure 3), but the F374A mutation blocks VX-809 action on F508del-CFTR. Login to comment
105 In addition, F374A also blocks the positive effect of S mutations on CFTR and F508del-CFTR biogenesis. Login to comment
153 (D) F374A L375A CFTR exhibits a folding defect that is not efficaciously suppressed by VX-809. Login to comment
157 CFTR 380 F374A ࢞371-375 % of Cont. Login to comment
162 380- CFTR 380 Trypsin (ug/ml) 25 20 15- - - - + Vehicle +VX-809 * CFTR 370 CFTR 370 2520- 15- CFTR 380 * +Vehicle + VX-809 ** ** + _ Wt _ VX-809 + _ + _ F374A L375A F374A L375A + _ ࢞371-375 Tub- C- BC- 100 4 108 6 115 2 12 8 7 B31 24 28 23 24 25 27 22 19 CFTR %-Wt C-band C. VX-809 0 5 10 15 _ ࢞371-375 -C -B CFTR Wt %-Wt 100 4 6 5 2 C-band 25 12 18 11 8 + CFTR 3800 25 2 1 7 3 0 25 2 1 7 3 D. Login to comment
175 (B) Mutation of F374A hinders the ability of misfolding suppressor mutations S2 and S3 to increase the efficacy of VX-809 on F508del-CFTR. Login to comment
176 (C) Mutation of F374A hinders the ability of S2 and S3 to increase accumulation of the folded C-band of CFTR. Login to comment
182 Vehicle VX-809 + + _ _ + + _ _ + + _ _ + + _ _ + + _ _ + + _ _ F508 F508 F374 F508 F374A S2 F508 F374A S3 F508 S2 F508 S3 + _ CFTR Tub- -C -B Wt C-100 1 12 2 4 3 4 1 3 1 42 8 51 B40 31 60 40 61 32 64 33 43 28 49 25 43 Vehicle VX-809 + + _ _ + + _ _ + + _ _ + + _ _ + + _ _ + _ F374A F374A S2 F374A S3 S2 S3 Tub- CFTR -C -B Wt C-100 9 80 8 158 7 162 136 182 163 225 B28 14 18 25 19 26 15 11 5 13 5 A. Login to comment
219 Soluble lysates were obtained by centrifugation at 20,000 &#d7; g combined mutation of F374A and L375A but efficaciously suppresses folding defects caused by each individual mutation. Login to comment