ABCC7 p.Asp1425*
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Localization of sequences within the C-terminal do... J Biol Chem. 2001 Jan 12;276(2):1291-8. Gentzsch M, Riordan JR
Localization of sequences within the C-terminal domain of the cystic fibrosis transmembrane conductance regulator which impact maturation and stability.
J Biol Chem. 2001 Jan 12;276(2):1291-8., 2001-01-12 [PMID:11022033]
Abstract [show]
Some disease-associated truncations within the 100-residue domain C-terminal of the second nucleotide-binding domain destabilize the mature protein (Haardt, M., Benharouga, M., Lechardeur, D., Kartner, N., and Lukacs, G. L. (1999) J. Biol. Chem. 274, 21873-21877). We now have identified three short oligopeptide regions in the C-terminal domain which impact cystic fibrosis transmembrane conductance regulator (CFTR) maturation and stability in different ways. A highly conserved hydrophobic patch (region I) formed by residues 1413-1416 (FLVI) was found to be crucial for the stability of the mature protein. Nascent chain stability was severely decreased by shortening the protein by 81 amino acids (1400X). This accelerated degradation was sensitive to proteasome inhibitors but not influenced by brefeldin A, indicating that it occurred at the endoplasmic reticulum. The five residues at positions 1400 to 1404 (region II) normally maintain nascent CFTR stability in a positional rather than a sequence-specific manner. A third modulating region (III) constituted by residues 1390 to 1394 destabilizes the protein. Hence the nascent form regains stability on further truncation back to residues 1390 or 1380, permitting some degree of maturation and a low level of cyclic AMP-stimulated chloride channel activity at the cell surface. Thus while not absolutely essential, the C-terminal domain strongly modulates the biogenesis and maturation of CFTR.
Comments [show]
None has been submitted yet.
No. Sentence Comment
25 The antisense primers introducing the stop codon were the following: A1440X, 5Ј-TGATATCGGGC- CCCTATTGCCGGAAGAGGCTCCTCTCGTT-3Ј; S1435X, 5Ј-TGATAT- CGGGCCCCTACCTCTCGTTCAGCAGTTTCTGGATGG-3Ј; L1430X, 5Ј-TGATATCGGGCCCCTATTTCTGGATGGAATCGTACTGCCGCAC- 3Ј; D1425X, 5Ј-TGATATCGGGCCCCTAGTACTGCCGCACTTTGTTC- TCTTCTATG-3Ј; K1420X, 5Ј-TGATATCGGGCCCCTAGTTCTCTTCT- ATGACCAAAAATTGTTGGC-3Ј; V1415X, 5Ј-TGATATCGGGCCCCTA- CAAAAATTGTTGGCATTCCAGCATTGC-3Ј; C1410X, 5Ј-TGATATCG- * This work was supported by National Institutes of Health, NIDDK Grant DK54076 and a Fellowship from the Deutsche Forschungsgemeinschaft (to M. G.).
X
ABCC7 p.Asp1425* 11022033:25:283
status: NEW[hide] Effects of C-terminal deletions on cystic fibrosis... Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1937-42. Epub 2003 Feb 10. Ostedgaard LS, Randak C, Rokhlina T, Karp P, Vermeer D, Ashbourne Excoffon KJ, Welsh MJ
Effects of C-terminal deletions on cystic fibrosis transmembrane conductance regulator function in cystic fibrosis airway epithelia.
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1937-42. Epub 2003 Feb 10., 2003-02-18 [PMID:12578973]
Abstract [show]
To better understand the function of the conserved C terminus of the cystic fibrosis (CF) transmembrane conductance regulator, we studied constructs containing deletions in the C-terminal tail. When expressed in well differentiated CF airway epithelia, each construct localized predominantly to the apical membrane and generated transepithelial Cl(-) current. The results suggested that neither the C-terminal PSD-95/Discs-large/ZO-1 (PDZ)-interacting motif nor other C-terminal sequences were absolutely required for apical expression in airway epithelia. Surprisingly, deleting an acidic cluster near the C terminus reduced both channel opening rate and transepithelial Cl(-) transport, indicating that it influences channel gating. These results may help explain the relative paucity of CF-associated mutations in the C terminus.
Comments [show]
None has been submitted yet.
No. Sentence Comment
116 A study in planar lipid bilayers reported little effect on open-state probability (Po) of D1425X or shorter deletions (22).
X
ABCC7 p.Asp1425* 12578973:116:90
status: NEW184 These findings are consistent with previous reports that maturation and degradation of C-terminally truncated CFTR (S1455X and D1425X) is similar to WT in COS and BHK cells (19-21).
X
ABCC7 p.Asp1425* 12578973:184:127
status: NEW