ABCC7 p.Glu407Cys
| ClinVar: |
c.1220A>T
,
p.Glu407Val
?
, not provided
|
| CF databases: |
c.1220A>T
,
p.Glu407Val
(CFTR1)
?
, The mutation was detected by multiplex heteroduplex analysis on the MDE gel matrix. It was found in one Canadian CF patient (second mutation: unknown).
|
| Predicted by SNAP2: | A: N (78%), C: N (57%), D: N (87%), F: D (53%), G: D (59%), H: N (57%), I: N (53%), K: N (72%), L: N (53%), M: N (53%), N: N (82%), P: D (63%), Q: N (82%), R: D (59%), S: N (78%), T: N (61%), V: N (82%), W: D (53%), Y: D (53%), |
| Predicted by PROVEAN: | A: N, C: D, D: 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, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Multiple membrane-cytoplasmic domain contacts in t... J Biol Chem. 2008 Sep 26;283(39):26383-90. Epub 2008 Jul 25. He L, Aleksandrov AA, Serohijos AW, Hegedus T, Aleksandrov LA, Cui L, Dokholyan NV, Riordan JR
Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating.
J Biol Chem. 2008 Sep 26;283(39):26383-90. Epub 2008 Jul 25., 2008-09-26 [PMID:18658148]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique ATP-binding cassette (ABC) ion channel mutated in patients with cystic fibrosis. The most common mutation, deletion of phenylalanine 508 (DeltaF508) and many other disease-associated mutations occur in the nucleotide binding domains (NBD) and the cytoplasmic loops (CL) of the membrane-spanning domains (MSD). A recently constructed computational model of the CFTR three-dimensional structure, supported by experimental data (Serohijos, A. W., Hegedus, T., Aleksandrov, A. A., He, L., Cui, L., Dokholyan, N. V., and Riordan, J. R. (2008) Proc. Natl. Acad. Sci. U. S. A. 105, 3256-3261) revealed that several of these mutations including DeltaF508 disrupted interfaces between these domains. Here we have used cysteine cross-linking experiments to verify all NBD/CL interfaces predicted by the structural model and observed that their cross-linking has a variety of different effects on channel gating. The interdomain contacts comprise aromatic clusters important for stabilization of the interfaces and also involve the Q-loops and X-loops that are in close proximity to the ATP binding sites. Cross-linking of all domain-swapping contacts between NBDs and MSD cytoplasmic loops in opposite halves of the protein rapidly and reversibly arrest single channel gating while those in the same halves have lesser impact. These results reinforce the idea that mediation of regulatory signals between cytoplasmic- and membrane-integrated domains of the CFTR channel apparently relies on an array of precise but highly dynamic interdomain structural joints.
Comments [show]
None has been submitted yet.
No. Sentence Comment
116 Based on the latter model, we attempted to detect cross-linking of the residue pairs V171C/E407C and V171C/L408C in the whole protein, but did not observe any indication of cross-linking of the mature band (supplemental Fig. S2A).
X
ABCC7 p.Glu407Cys 18658148:116:91
status: NEW125 We found similar results for the Cys pair V171C and E407C (supplemental Fig. 2B), but not with a Cys pair introduced at Gln-958 and Leu-1261 (supplemental Fig. S2C), confirming that the faster moving CFTR fragment was indeed due to the cross-linking at the CL1/NBD1 interface.
X
ABCC7 p.Glu407Cys 18658148:125:52
status: NEW244 We have verified the latter conformation by introducing Cys pairs in CL1 and different residues in RI (V171C/ E407C, V171C/L408C) and showing that these pairs can be cross-linked by M8M (Fig. 3B).
X
ABCC7 p.Glu407Cys 18658148:244:110
status: NEW