ABCC7 p.Phe508Lys
| ClinVar: |
c.1523T>C
,
p.Phe508Ser
?
, not provided
c.1523T>G , p.Phe508Cys N , Benign |
| CF databases: |
c.1521_1523delCTT
,
p.Phe508del
D
, CF-causing
c.1523T>C , p.Phe508Ser (CFTR1) D , This mutation was found in a patient with CBAVD. c.1523T>G , p.Phe508Cys (CFTR1) ? , |
| Predicted by SNAP2: | A: D (95%), C: D (75%), D: D (95%), E: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| 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: D, |
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[hide] Side chain and backbone contributions of Phe508 to... Nat Struct Mol Biol. 2005 Jan;12(1):10-6. Epub 2004 Dec 26. Thibodeau PH, Brautigam CA, Machius M, Thomas PJ
Side chain and backbone contributions of Phe508 to CFTR folding.
Nat Struct Mol Biol. 2005 Jan;12(1):10-6. Epub 2004 Dec 26., [PMID:15619636]
Abstract [show]
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.
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No. Sentence Comment
92 The known polymorphism F508C and the non-CF-causing variant F508S both showed measurable quantities of band C at steady-state levels, as would be expected for non-CF-causingsubstitutions.Thehydrophobicaminoacidsubstitutions F508I,F508W and F508Y did not produce substantial steady-state levels of band C as measured by western blotting, nor did the ionizable amino acid substitutions F508D, F508E, F508K, F508H or F508R.
X
ABCC7 p.Phe508Lys 15619636:92:398
status: NEW113 W ild type ∆∆F508 F508 F508D F508K F508E F508R F508H F508S F508T F508N F508Q C B Charged Polar F508A F508C F508I F508L ∆F508 F508 W ild type C B F508W F508Y F508G F508P Hydrophobic F508M F508V ̅̆ ̆ ̅ Figure 3 Maturation of full-length CFTR mutants.
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ABCC7 p.Phe508Lys 15619636:113:43
status: NEW[hide] The cystic fibrosis-causing mutation deltaF508 aff... J Biol Chem. 2010 Nov 12;285(46):35825-35. Epub 2010 Jul 28. Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL, Kirk K, Thomas PJ
The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.
J Biol Chem. 2010 Nov 12;285(46):35825-35. Epub 2010 Jul 28., 2010-11-12 [PMID:20667826]
Abstract [show]
The deletion of phenylalanine 508 in the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator is directly associated with >90% of cystic fibrosis cases. This mutant protein fails to traffic out of the endoplasmic reticulum and is subsequently degraded by the proteasome. The effects of this mutation may be partially reversed by the application of exogenous osmolytes, expression at low temperature, and the introduction of second site suppressor mutations. However, the specific steps of folding and assembly of full-length cystic fibrosis transmembrane conductance regulator (CFTR) directly altered by the disease-causing mutation are unclear. To elucidate the effects of the DeltaF508 mutation, on various steps in CFTR folding, a series of misfolding and suppressor mutations in the nucleotide binding and transmembrane domains were evaluated for effects on the folding and maturation of the protein. The results indicate that the isolated NBD1 responds to both the DeltaF508 mutation and intradomain suppressors of this mutation. In addition, identification of a novel second site suppressor of the defect within the second transmembrane domain suggests that DeltaF508 also effects interdomain interactions critical for later steps in the biosynthesis of CFTR.
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No. Sentence Comment
61 In addition, the ability of a novel second-site suppressor, located within TMD2, to rescue the ⌬F508 and F508K mutants demonstrates that proper domain-domain assembly is critical to CFTR maturation.
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ABCC7 p.Phe508Lys 20667826:61:112
status: NEW114 The inclusion of the -3M mutations failed to significantly rescue the folding of the F508D and F508K mutants, suggesting that the -3M suppressors do not directly influence the interaction between NBD1 and other domains of CFTR (Fig. 1B).
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ABCC7 p.Phe508Lys 20667826:114:95
status: NEW230 To evaluate the potential mechanisms by which the R1070W mutation rescued ⌬F508, this mutation was also introduced into the ⌬F508-3M and F508K backgrounds (Fig. 6, C and D).
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ABCC7 p.Phe508Lys 20667826:230:151
status: NEW231 F508K is expected to disrupt the interdomain interaction, as it interferes with maturation but does not affect the isolated NBD1 (26).
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ABCC7 p.Phe508Lys 20667826:231:0
status: NEW234 In this regard, the R1070W mutation induced the formation of Band C in the F508K mutant predicted to disrupt the interdomain interaction, an effect not seen for low temperature or with the -3M mutations (Fig. 6D).
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ABCC7 p.Phe508Lys 20667826:234:75
status: NEW250 The suppression of the ⌬F508 and F508P substitutions, but not the F508D and F508K mutants, indicates that these mutations alter CFTR folding by discrete mechanisms or are of differing severities.
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ABCC7 p.Phe508Lys 20667826:250:83
status: NEW308 Mutations in ICL4 at position 1070 were evaluated for effects on the trafficking of wild type, ⌬F508, and F508K CFTR, transiently expressed in HEK293 cells.
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ABCC7 p.Phe508Lys 20667826:308:113
status: NEW313 Two views, rotated by 90 degrees are shown. B, Western blots show the effects of the ICL4 Arg-1070 mutations on the trafficking of wild type, ⌬F508, and F508K CFTR.
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ABCC7 p.Phe508Lys 20667826:313:160
status: NEW316 D, trafficking of the F508K missense protein was evaluated with the R1070W mutation.
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ABCC7 p.Phe508Lys 20667826:316:22
status: NEW317 Trafficking of F508K was partially rescued by the R1070W mutation.
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ABCC7 p.Phe508Lys 20667826:317:15
status: NEW344 Maturation of the F508K CFTR molecule was potentially facilitated by interactions between the indole side chain from R1070W and the NBD1 surface.
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ABCC7 p.Phe508Lys 20667826:344:18
status: NEW[hide] Requirements for efficient correction of DeltaF508... Cell. 2012 Jan 20;148(1-2):164-74. doi: 10.1016/j.cell.2011.11.023. Mendoza JL, Schmidt A, Li Q, Nuvaga E, Barrett T, Bridges RJ, Feranchak AP, Brautigam CA, Thomas PJ
Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences.
Cell. 2012 Jan 20;148(1-2):164-74. doi: 10.1016/j.cell.2011.11.023., [PMID:22265409]
Abstract [show]
Misfolding of DeltaF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the DeltaF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores DeltaF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.
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No. Sentence Comment
187 See also Table S2. (C) F508K, F508R, and F508K in combination with I539T, G550E, R553M, R555K, and 3M mutations increase folding yield of NBD1, but exhibit no corresponding increase in CFTR maturation yield (dark blue circles and line, m = 0.03, R = 0.40) (&#b1;SEM, n = 9 along x axis and n = 3 along y axis).
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ABCC7 p.Phe508Lys 22265409:187:23
status: NEWX
ABCC7 p.Phe508Lys 22265409:187:41
status: NEW197 The experiments with the second-site suppressor mutations on the F508K background demonstrate, regardless of how well NBD1 folds, CFTR is unable to mature if the NBD1-ICL4 is disrupted.
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ABCC7 p.Phe508Lys 22265409:197:65
status: NEW241 On the WT or DF508 CFTR models, F508K, R1070, R1070W residues were modeled using the PyMOL (Schrodinger, 2010) mutagenesis function (Figures 1B, 2B, rightmost panel, 5, 6, and S1).
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ABCC7 p.Phe508Lys 22265409:241:32
status: NEW