ABCC7 p.Leu1480Ala
CF databases: |
c.4439T>C
,
p.Leu1480Pro
(CFTR1)
?
, The mutation was detected by DGGE analysis and characterized by direct sequencing. We have seen it only twice, in over 2000 control chromosomes from Italian population.
|
Predicted by SNAP2: | A: N (53%), C: N (61%), D: D (59%), E: D (53%), F: N (57%), G: D (63%), H: D (53%), I: N (72%), K: D (59%), M: N (78%), N: D (53%), P: D (66%), Q: N (61%), R: D (63%), S: N (53%), T: N (57%), V: N (78%), W: D (59%), Y: N (53%), |
Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Regulation of cystic fibrosis transmembrane conduc... Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1300-5. Epub 2001 Jan 23. Raghuram V, Mak DO, Foskett JK
Regulation of cystic fibrosis transmembrane conductance regulator single-channel gating by bivalent PDZ-domain-mediated interaction.
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1300-5. Epub 2001 Jan 23., 2001-01-30 [PMID:11158634]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent protein kinase- and ATP-regulated chloride channel, the activity of which determines the rate of electrolyte and fluid transport in a variety of epithelial tissues. Here we describe a mechanism that regulates CFTR channel activity, which is mediated by PDZ domains, a family of conserved protein-interaction modules. The Na(+)/H(+) exchanger regulatory factor (NHERF) binds to the cytoplasmic tail of CFTR through either of its two PDZ (PDZ1 and PDZ2) domains. A recombinant fragment of NHERF (PDZ1-2) containing the two PDZ domains increases the open probability (P(o)) of single CFTR channels in excised membrane patches from a lung submucosal gland cell line. Both PDZ domains are required for this functional effect, because peptides containing mutations in either domain are unable to increase channel P(o). The concentration dependence of the regulation by the bivalent PDZ1-2 domain is biphasic, i.e., activating at lower concentrations and inhibiting at higher concentrations. Furthermore, either PDZ domain alone or together is without effect on P(o), but either domain can competitively inhibit the PDZ1-2-mediated stimulation of CFTR. Our results support a molecular model in which bivalent NHERF PDZ domains regulate channel gating by crosslinking the C-terminal tails in a single dimeric CFTR channel, and the magnitude of this regulation is coupled to the stoichiometry of these interactions.
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No. Sentence Comment
61 [35 S]methionine-labeled full-length CFTR and CFTR-L1480A (Leu-1480 was replaced by Ala) was prepared by using an SP6 TnT (Promega) kit in the presence of canine pancreatic microsomes (Promega).
X
ABCC7 p.Leu1480Ala 11158634:61:51
status: NEWX
ABCC7 p.Leu1480Ala 11158634:61:59
status: NEW110 The mutation L1480A resulted in a complete loss of interaction, and mutations T1378A, L1480V, and L1480M resulted in markedly reduced interaction (Fig. 1D), with both PDZ1 and PDZ2 having similar specificities for their target ligands.
X
ABCC7 p.Leu1480Ala 11158634:110:13
status: NEW112 However, there are no additional PDZ binding sites in CFTR, because the PDZ1-2 domains bound to full-length in vitro-translated CFTR but not to mutant CFTR (L1480A) (Fig. 1C).
X
ABCC7 p.Leu1480Ala 11158634:112:157
status: NEW142 [35S]methionine-labeled in vitro-translated products (I) and the GST-PDZ1-2 (1-299) ''pull-down`` products (P) of wild-type CFTR (WT) and mutant CFTR (L1480A) are indicated.
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ABCC7 p.Leu1480Ala 11158634:142:151
status: NEW[hide] Accessory protein facilitated CFTR-CFTR interactio... Cell. 2000 Sep 29;103(1):169-79. Wang S, Yue H, Derin RB, Guggino WB, Li M
Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity.
Cell. 2000 Sep 29;103(1):169-79., [PMID:11051556]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a chloride channel protein that belongs to the superfamily of ATP binding cassette (ABC) transporters. Phosphorylation by protein kinase A in the presence of ATP activates the CFTR-mediated chloride conductance of the apical membranes. We have identified a novel hydrophilic CFTR binding protein, CAP70, which is also concentrated on the apical surfaces. CAP70 consists of four PDZ domains, three of which are capable of binding to the CFTR C terminus. Linking at least two CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein.
Comments [show]
None has been submitted yet.
No. Sentence Comment
113 The amino acid substitution of leucine with alanine at the C-terminal end (L1480A) was designated as HA-CFTR-Ct*.
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ABCC7 p.Leu1480Ala 11051556:113:75
status: NEW157 (f and g) Open probability (Po) and mean opening time (MOT) of the wild-type CFTR and mutated CFTR-L1480A are plotted against different concentrations of purified recombinant CAP70 protein: filled squares, wild-type CFTR plus CAP70; filled circles, CFTR (L1480A) plus CAP70; open circles, wild-type CFTR plus PDZ3-3.
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ABCC7 p.Leu1480Ala 11051556:157:99
status: NEWX
ABCC7 p.Leu1480Ala 11051556:157:255
status: NEW159 n for wild-type CFTR is 5d51;9, for CFTR/L1480A is 4 and for PDZ3-3 is 5.
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ABCC7 p.Leu1480Ala 11051556:159:44
status: NEW212 substitution of the last residue leucine with alanine these possibilities, we tested the effect of a tandem PDZ3 domain protein (PDZ3-3) on CFTR channel activ- (L1480A) in CFTR, which abolishes the binding to CAP70, completely eliminated the CAP70-mediated po- ity.
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ABCC7 p.Leu1480Ala 11051556:212:161
status: NEW278 The CFTR-L1480A was derived bind to the C terminus of CFTR (Hall et al., 1998; Short from the pRSV-CFTR by replacing the HpaI/ApaI fragment with a et al., 1998; Wang et al., 1998).
X
ABCC7 p.Leu1480Ala 11051556:278:9
status: NEW