ABCC7 p.Asn1419Ser
| Predicted by SNAP2: | A: N (53%), C: N (82%), D: N (87%), E: D (53%), F: D (66%), G: N (97%), H: N (53%), I: D (63%), K: D (66%), L: D (63%), M: D (59%), P: D (66%), Q: N (53%), R: D (71%), S: N (93%), T: N (53%), V: N (53%), W: D (71%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, P: N, Q: N, R: N, S: N, T: N, V: D, W: N, Y: D, |
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[hide] Folding and rescue of a cystic fibrosis transmembr... J Biol Chem. 2010 Aug 27;285(35):27033-44. Epub 2010 Jun 15. Da Paula AC, Sousa M, Xu Z, Dawson ES, Boyd AC, Sheppard DN, Amaral MD
Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins.
J Biol Chem. 2010 Aug 27;285(35):27033-44. Epub 2010 Jun 15., 2010-08-27 [PMID:20551307]
Abstract [show]
Impairment of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel causes cystic fibrosis, a fatal genetic disease. Here, to gain insight into CFTR structure and function, we exploited interspecies differences between CFTR homologues using human (h)-murine (m) CFTR chimeras containing murine nucleotide-binding domains (NBDs) or regulatory domain on an hCFTR backbone. Among 15 hmCFTR chimeras analyzed, all but two were correctly processed, one containing part of mNBD1 and another containing part of mNBD2. Based on physicochemical distance analysis of divergent residues between human and murine CFTR in the two misprocessed hmCFTR chimeras, we generated point mutations for analysis of respective CFTR processing and functional properties. We identified one amino acid substitution (K584E-CFTR) that disrupts CFTR processing in NBD1. No single mutation was identified in NBD2 that disrupts protein processing. However, a number of NBD2 mutants altered channel function. Analysis of structural models of CFTR identified that although Lys(584) interacts with residue Leu(581) in human CFTR Glu(584) interacts with Phe(581) in mouse CFTR. Introduction of the murine residue (Phe(581)) in cis with K584E in human CFTR rescued the processing and trafficking defects of K584E-CFTR. Our data demonstrate that human-murine CFTR chimeras may be used to validate structural models of full-length CFTR. We also conclude that hmCFTR chimeras are a valuable tool to elucidate interactions between different domains of CFTR.
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No. Sentence Comment
278 Nevertheless, as discussed above, N1419S alone likely rescues the processing defect of 114c-NBD2.
X
ABCC7 p.Asn1419Ser 20551307:278:34
status: NEW279 This argues that the interacting residues of N1419S cause the trafficking defect of the hmCFTR chimera 114c-NBD2.
X
ABCC7 p.Asn1419Ser 20551307:279:45
status: NEW