ABCC7 p.Lys978Arg
| ClinVar: |
c.2932A>T
,
p.Lys978*
D
, Likely pathogenic
|
| Predicted by SNAP2: | A: D (71%), C: D (75%), D: D (91%), E: D (85%), F: D (85%), G: D (80%), H: D (71%), I: D (75%), L: D (80%), M: D (63%), N: D (71%), P: D (91%), Q: D (75%), R: D (66%), S: D (66%), T: D (75%), V: D (80%), W: D (91%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, L: D, M: D, N: N, P: D, Q: N, R: N, S: N, T: D, V: D, W: D, Y: D, |
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[hide] COMMD1-mediated ubiquitination regulates CFTR traf... PLoS One. 2011 Mar 31;6(3):e18334. Drevillon L, Tanguy G, Hinzpeter A, Arous N, de Becdelievre A, Aissat A, Tarze A, Goossens M, Fanen P
COMMD1-mediated ubiquitination regulates CFTR trafficking.
PLoS One. 2011 Mar 31;6(3):e18334., [PMID:21483833]
Abstract [show]
The CFTR (cystic fibrosis transmembrane conductance regulator) protein is a large polytopic protein whose biogenesis is inefficient. To better understand the regulation of CFTR processing and trafficking, we conducted a genetic screen that identified COMMD1 as a new CFTR partner. COMMD1 is a protein associated with multiple cellular pathways, including the regulation of hepatic copper excretion, sodium uptake through interaction with ENaC (epithelial sodium channel) and NF-kappaB signaling. In this study, we show that COMMD1 interacts with CFTR in cells expressing both proteins endogenously. This interaction promotes CFTR cell surface expression as assessed by biotinylation experiments in heterologously expressing cells through regulation of CFTR ubiquitination. In summary, our data demonstrate that CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane. Thus, increasing COMMD1 expression may provide an approach to simultaneously inhibit ENaC absorption and enhance CFTR trafficking, two major issues in cystic fibrosis.
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No. Sentence Comment
114 Three lysines were mutated to arginine in the ICL3 domain near Ser-945 (K946R and K951R) and Asp-979 (K978R).
X
ABCC7 p.Lys978Arg 21483833:114:102
status: NEW117 The difference between mock-transfected and COMMD1- transfected cells was not significant in the case of mutant K978R-CFTR.
X
ABCC7 p.Lys978Arg 21483833:117:112
status: NEW172 (A) HeLa cells were transfected with CFTR constructs (wt, K946R, K951R or K978R-CFTR) and Myc-COMMD1 or empty vector as control (mock).
X
ABCC7 p.Lys978Arg 21483833:172:74
status: NEW180 (C) Representative gels for the same co-immunoprecipitation experiment between COMMD1 and wt, K946R, K951R or K978R-CFTR in heterologous system. HeLa cells were co-transfected with Myc-COMMD1 or empty vector (mock) and wt, K946R, K951R or K978R-CFTR.
X
ABCC7 p.Lys978Arg 21483833:180:110
status: NEWX
ABCC7 p.Lys978Arg 21483833:180:239
status: NEW[hide] CFTR inhibition by glibenclamide requires a positi... Biochim Biophys Acta. 2007 Oct;1768(10):2438-46. Epub 2007 May 21. Melin P, Hosy E, Vivaudou M, Becq F
CFTR inhibition by glibenclamide requires a positive charge in cytoplasmic loop three.
Biochim Biophys Acta. 2007 Oct;1768(10):2438-46. Epub 2007 May 21., [PMID:17582383]
Abstract [show]
The sulfonylurea glibenclamide is widely used as an open-channel blocker of the CFTR chloride channel. Here, we used site-directed mutagenesis to identify glibenclamide site of interaction: a positively charged residue K978, located in the cytoplasmic loop 3. Charge-neutralizing mutations K978A, K978Q, K978S abolished the inhibition of forskolin-activated CFTR chloride current by glibenclamide but not by CFTR(inh)-172. The charge-conservative mutation K978R did not alter glibenclamide sensitivity of CFTR current. Mutations of the neighbouring R975 (R975A, R975S, R975Q) did not affect electrophysiological and pharmacological properties of CFTR. No alteration of halide selectivity was observed with any of these CFTR mutant channels. This study identifies a novel potential inhibitor site within the CFTR molecule, and suggests a novel role of cytoplasmic loop three, within the second transmembrane domain of CFTR protein. This work is the first to report on the role of a residue in a cytoplasmic loop in the mechanism of action of the channel blocker glibenclamide.
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No. Sentence Comment
3 The charge-conservative mutation K978R did not alter glibenclamide sensitivity of CFTR current.
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ABCC7 p.Lys978Arg 17582383:3:33
status: NEW77 We investigated the role of the charged residue K978 in the sequence ILNRFSKD of CL3 (Fig. 1B) described as a region physically close to the pore [29] and examined the interaction of glibenclamide with mutated EGFP-CFTR channels: K978A, K978Q, K978R, Fig. 2.
X
ABCC7 p.Lys978Arg 17582383:77:244
status: NEW84 Similar effects in the presence of Fsk were recorded with cells expressing K978A, K978Q, K978R and K978S mutants CFTR.
X
ABCC7 p.Lys978Arg 17582383:84:89
status: NEW96 To investigate the role of the charge of the side chain of K978 in glibenclamide resistance, different amino acid substitutions were examined: K978A, K978Q, K978R.
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ABCC7 p.Lys978Arg 17582383:96:157
status: NEW98 Fig. 4A presents the ratio Iglib/Ifsk, recorded at -100 mV, with 100 bc;M glibenclamide, for K978A, K978Q, K978R, K978S channels compared to CFTR-wt.
X
ABCC7 p.Lys978Arg 17582383:98:110
status: NEW100 Indeed, the ratio at -100 mV for the charge conservative mutant K978R (0.17&#b1; 0.04, n=4) was not significantly different from that of CFTR-wt.
X
ABCC7 p.Lys978Arg 17582383:100:64
status: NEW140 In contrast, substitution of lysine 978 with another positively charged residue (K978R) had no incidence on glibenclamide sensitivity of CFTR channels. This charge conservative mutant shared the same properties of inhibition as CFTRwt.
X
ABCC7 p.Lys978Arg 17582383:140:81
status: NEW