ABCMdb

ABCC7 p.Tyr577Glu

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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Publications
[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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Sentences [show]
No. Sentence Comment
220 c, overlay of spectra of Y577E NBD1 èc;RIèc;RE recorded at 1.9 mM (black) and 0.1 mM (red). Login to comment
236 Interestingly, a Y577E mutant did not result in significant broadening of Cys-491 and Trp-496 resonances relative to WT or to significant concentration-dependent chemical shift perturbations (Fig. 6c). Login to comment
238 Visual inspection indicates changes in linewidth and relative peak intensity throughout the Y577E spectra at 0.1 and 1.9 mM, strongly hinting that significant dimerization is occurring in this mutant. Login to comment
268 Mutations at the dimer interface (Y577K and Y577E) also affect the Q-loop segment conformational sampling. Login to comment
373 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. Login to comment