ABCC7 p.Gln637Ala
| ClinVar: |
c.1909C>T
,
p.Gln637*
?
, not provided
|
| Predicted by SNAP2: | A: N (87%), C: N (72%), D: N (87%), E: N (97%), F: N (53%), G: N (87%), H: N (93%), I: N (82%), K: N (97%), L: N (82%), M: N (87%), N: N (93%), P: N (82%), R: N (97%), S: N (93%), T: N (87%), V: N (87%), W: D (53%), Y: N (82%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: N, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, R: N, S: N, T: N, V: D, W: D, Y: N, |
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[hide] NMR evidence for differential phosphorylation-depe... EMBO J. 2010 Jan 6;29(1):263-77. Epub 2009 Nov 19. Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD
NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR.
EMBO J. 2010 Jan 6;29(1):263-77. Epub 2009 Nov 19., 2010-01-06 [PMID:19927121]
Abstract [show]
The most common cystic fibrosis (CF)-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of Phe508 (DeltaF508) in the first of two nucleotide-binding domains (NBDs). Nucleotide binding and hydrolysis at the NBDs and phosphorylation of the regulatory (R) region are required for gating of CFTR chloride channel activity. We report NMR studies of wild-type and DeltaF508 murine CFTR NBD1 with the C-terminal regulatory extension (RE), which contains residues of the R region. Interactions of the wild-type NBD1 core with the phosphoregulatory regions, the regulatory insertion (RI) and RE, are disrupted upon phosphorylation, exposing a potential binding site for the first coupling helix of the N-terminal intracellular domain (ICD). Phosphorylation of DeltaF508 NBD1 does not as effectively disrupt interactions with the phosphoregulatory regions, which, along with other structural differences, leads to decreased binding of the first coupling helix. These results provide a structural basis by which phosphorylation of CFTR may affect the channel gating of full-length CFTR and expand our understanding of the molecular basis of the DeltaF508 defect.
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No. Sentence Comment
107 Significant conformational changes, apart from differences in the local surface properties at the mutation site, were not observed in the crystal structures of DF508 NBD1-RE (also containing F429S, F494N, and Q637A mutations required for protein solubility and crystallization) (Lewis et al, 2004, 2005) and of DF508 NBD1 lacking the RI and the RE (PDB code 2PZF).
X
ABCC7 p.Gln637Ala 19927121:107:209
status: NEW249 The additional mutations (F494N, Q637A or F429S, F494N, and Q637R) in the DF508 NBD1-RE construct required for protein solubility and crystallization (Lewis et al, 2005) also partially rescue the trafficking and gating defects of full-length DF508 CFTR, suggesting that the crystal structure of DF508 NBD1-RE may correspond to a partially corrected conformation (Pissarra et al, 2008).
X
ABCC7 p.Gln637Ala 19927121:249:33
status: NEW