ABCC7 p.Tyr577Lys
| ClinVar: |
c.1731C>T
,
p.Tyr577=
D
, Likely pathogenic
c.1730A>T , p.Tyr577Phe ? , not provided |
| CF databases: |
c.1730A>T
,
p.Tyr577Phe
(CFTR1)
?
, Mutation Y577F and 1874insT were found together in another CF patient from Austria; this boy is also heterozygous for [delta]F508.
|
| Predicted by SNAP2: | A: D (59%), C: N (61%), D: D (71%), E: D (63%), F: N (82%), G: D (71%), H: N (78%), I: N (61%), K: D (63%), L: N (66%), M: N (53%), N: D (59%), P: D (80%), Q: N (57%), R: D (59%), S: D (63%), T: D (53%), V: N (66%), W: N (57%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, |
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[hide] Deletion of Phenylalanine 508 in the First Nucleot... J Biol Chem. 2015 Sep 18;290(38):22862-78. doi: 10.1074/jbc.M115.641134. Epub 2015 Jul 6. Chong PA, Farber PJ, Vernon RM, Hudson RP, Mittermaier AK, Forman-Kay JD
Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization.
J Biol Chem. 2015 Sep 18;290(38):22862-78. doi: 10.1074/jbc.M115.641134. Epub 2015 Jul 6., [PMID:26149808]
Abstract [show]
Deletion of Phe-508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) results in destabilization of the domain, intramolecular interactions involving the domain, and the entire channel. The destabilization caused by F508del manifests itself in defective channel processing and channel gating defects. Here, we present NMR studies of the effect of F508del and the I539T stabilizing mutation on NBD1 dynamics, with a view to understanding these changes in stability. Qualitatively, F508del NMR spectra exhibit significantly more peak broadening than WT spectra due to the enhanced intermediate time scale (millisecond to microsecond) motions in the mutant. Unexpectedly, studies of fast (nanosecond to picosecond) motions revealed that F508del NBD1 tumbles more rapidly in solution than WT NBD1. Whereas F508del tumbles at a rate nearly consistent with the monomeric state, the WT protein tumbles significantly more slowly. Paramagnetic relaxation enhancement experiments confirm that NBD1 homodimerizes in solution in the expected head-to-tail orientation. NMR spectra of WT NBD1 reveal significant concentration-dependent chemical shift perturbations consistent with NBD1 dimerization. Chemical shift analysis suggests that the more rapid tumbling of F508del is the result of an impaired ability to dimerize. Based on previously published crystal structures and NMR spectra of various NBD1 mutants, we propose that deletion of Phe-508 affects Q-loop conformational sampling in a manner that inhibits dimerization. These results provide a potential mechanism for inhibition of channel opening by F508del and support the dimer interface as a target for cystic fibrosis therapeutics.
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No. Sentence Comment
218 b, overlay of spectra of Y577K NBD1 èc;RIèc;RE recorded at 1.7 mM (black) and 0.1 mM (red).
X
ABCC7 p.Tyr577Lys 26149808:218:25
status: NEW234 Peaks corresponding to the amide groups of Gly-486, Cys-491, Gly-509, and Gly-551 and the Trp-496 indole NঈH, which have the largest concentration-dependent chemical shift perturbations in the WT, become invisible at high concentrations and nearly so at low concentrations for the Y577K NBD1 mutant (Fig. 6b).
X
ABCC7 p.Tyr577Lys 26149808:234:287
status: NEW235 Although the effect of Y577K on the amount of dimer is unclear from these experiments, this mutation in the dimer interface has a pronounced effect (i.e. extensive broadening) on Gly-486, Cys-491, Trp-496, and Gly-509 confirming that it is reasonable to interpret the concentration-dependent chemical shift perturbations at these residues in the WT as a response to dimerization at the expected interface.
X
ABCC7 p.Tyr577Lys 26149808:235:23
status: NEW239 Combined with observations seen in Y577K, these data indicate that chemical shift perturbations at Ser-485, Gly-486, Cys-491, Trp-496, and Gly-509 are linked to changes at the presumed heterodimer interface.
X
ABCC7 p.Tyr577Lys 26149808:239:35
status: NEW268 Mutations at the dimer interface (Y577K and Y577E) also affect the Q-loop segment conformational sampling.
X
ABCC7 p.Tyr577Lys 26149808:268:34
status: NEW334 Evidence supporting the connection between dimerization and the Phe-508 position comes from the large concentration-dependent chemical shift change of the adjacent residue Gly-509 (b03;30 Hz) seen in WT spectra (Fig. 6a) and the concentration-dependent broadening of this signal in the Y577K spectra (Fig. 6b).
X
ABCC7 p.Tyr577Lys 26149808:334:289
status: NEW373 Furthermore, mutations in the dimer interface (Y577K and Y577E) clearly alter the Q-loop segment equilibrium, with changes observed as far away from the dimer interface as Gly-509, which is adjacent to the Phe-508 position.
X
ABCC7 p.Tyr577Lys 26149808:373:47
status: NEW