ABCMdb

ABCC7 p.Lys1060Ala

ClinVar:	c.3179A>C , p.Lys1060Thr ? , not provided
CF databases:	c.3179A>C , p.Lys1060Thr (CFTR1) D , This mutation was detected by DGGE analysis and identified by direct sequencing. This mutation was found in one Spanish man with CBAVD.
Predicted by SNAP2:	A: N (53%), C: N (61%), D: D (71%), E: D (59%), F: D (66%), G: D (59%), H: N (66%), I: N (53%), L: D (53%), M: N (53%), N: D (53%), P: D (71%), Q: N (87%), R: N (87%), S: D (53%), T: N (57%), V: D (53%), W: D (71%), Y: D (53%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N,

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Publications
[hide] CFTR: effect of ICL2 and ICL4 amino acids in close... J Cyst Fibros. 2013 Dec;12(6):737-45. doi: 10.1016/j.jcf.2013.02.002. Epub 2013 Mar 9. Billet A, Mornon JP, Jollivet M, Lehn P, Callebaut I, Becq F
CFTR: effect of ICL2 and ICL4 amino acids in close spatial proximity on the current properties of the channel.
J Cyst Fibros. 2013 Dec;12(6):737-45. doi: 10.1016/j.jcf.2013.02.002. Epub 2013 Mar 9., [PMID:23478129]

Abstract [show]
BACKGROUND: CFTR is the only ABC transporter functioning as a chloride (Cl(-)) channel. We studied molecular determinants, which might distinguish CFTR from standard ABC transporters, and focused on the interface formed by the intracellular loops from the membrane spanning domains. METHODS: Residues from ICL2 and ICL4 in close proximity were targeted, and their involvement in the functioning of CFTR was studied by whole cell patch clamp recording. RESULTS: We identified 2 pairs of amino acids, at the extremity of the bundle formed by the four intracellular loops, whose mutation i) decreases the Cl(-) current of CFTR (couple E267-K1060) or ii) increases it with a change of the electrophysiological signature (couple S263-V1056). CONCLUSIONS: These results highlight the critical role of these ICL residues in the assembly of the different domains and/or in the Cl(-) permeation pathway of CFTR.

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Sentences [show]
No. Sentence Comment
72 In order to change the properties of the side chains, we replaced each amino acid by a small, uncharged residue (mutants E267A-CFTR and K1060A-CFTR) or by an oppositely charged residue (mutants E267R-CFTR, K1060E-CFTR). Login to comment
86 100 200 -50 50 100 -100 100 100 100 200 C D B A I (pA/pF) I (pA/pF) I (pA/pF) V (mV) V (mV) V (mV) 5000pA 50ms E267R-K1060E E267A E267R K1060A K1060E E267A E267R wt E267R-K1060E K1060A K1060E ICL4 ICL2 K1060 E267 ICL1 ICL3 K1060 E267 ICL4 ICL2 ICL1 ICL3 % of maturation B C wt E267A E267R K1060A K1060E E267R-K1060E wt -50 50 100 -100 100 200 -50 50 100 -100 100 Fig. 2. Login to comment
93 Dotted lines represent a maturation similar to that of the wt protein (C, D) Whole cell chloride currents of HEK293 cells expressing wt-CFTR, E267A/R-, K1060A/Eor E267R-K1060E-CFTR mutants in presence of 10 bc;M Fsk. Login to comment
107 For K1060, irrespective of the replacement of the positively charged side chain by a small uncharged residue (K1060A mutant) or a negatively charged residue (K1060E mutant), the inward and outward Cl-current densities were 50-60% lower than the corresponding Cl-currents elicited by wt channels but similar to that of the E267A mutant. Login to comment
137 We observed that the abolition of one charged residue in the E267A or K1060A mutants induced a 50% diminution of the Cl-current density (Fig. 2). Login to comment