ABCMdb

ABCC7 p.Phe508Met

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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Publications
[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
33 The F508A,F508M,F508P,F508D,F508Q,F508R and F508S mutant proteins were more similar to the wild type than the ∆F508 protein in their temperature-dependence of refolding (Fig. 1b,c). Login to comment
43 The missense mutant proteins F508A, F508M,F508P,F508D,F508Q,F508R and F508S had similar ∆Gunfolding and m-values, 3.4-3.8 kcal mol-1 and 1.5-1.7 kcal mol-1 M-1 denaturant, respectively, highlighting the fact that changes in the bulk or chemical properties of the substituted side chain had little effect on the native-state stabilities of these domains as measured by denaturation with GuHCl (Table 1). Login to comment
46 How does the isolated NBD accommodate such Temperature (ºC) 4 10 16 22 Fractionalyield 0.0 0.5 1.0 Temperature (ºC) 4 10 16 22 Temperature (ºC) 4 10 16 22 Wild type ∆F508 Wild type ∆F508 ̄ F508A ̄ F508M F508P F508W ͷ F508W W496F Wild type ∆F508 F508Q F508R F508D F508S a b c Figure 1 NBD1 folding efficiency as a function of folding temperature. Login to comment
53 Table 1 Stability of wild-type and mutant NBD proteins Protein ∆Gunfolding ∆∆Gunfolding m-value (kcal mol-1) (kcal mol-1) (kcal mol-1 M-1) Wild type 3.7 ± 0.1 0 1.7 ∆F508 3.6 ± 0.1 0.1 1.7 F508A 3.6 ± 0.2 0.1 1.6 F508M 3.5 ± 0.1 0.1 1.6 F508P 3.5 ± 0.3 0.2 1.6 F508D 3.6 ± 0.1 0.1 1.6 F508Q 3.5 ± 0.2 0.2 1.6 F508R 3.4 ± 0.3 0.3 1.6 F508S 3.8 ± 0.2 -0.1 1.6 considerable changes in amino acid character at position 508 when this position is critical to the proper biogenesis of the full-length protein, and what are the underlying structural changes associated with these substitutions? Login to comment
90 The steady-state band C levels of F508C and F508M were reduced, but closest to those of wild type. Login to comment
113 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. Login to comment