ABCMdb

ABCC7 p.Val1293Gly

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Publications

PMID: 17244607 [PubMed] Zegarra-Moran O et al: "Functional analysis of mutations in the putative binding site for cystic fibrosis transmembrane conductance regulator potentiators. Interaction between activation and inhibition."

No. Sentence Comment

6 In R553Q and V1293G mutants, the dissociation constant of potentiators for the activating site was increased, whereas the dissociation constant for the inhibitory site was reduced. Login to comment
44 We found that the stimulating effect of potentiators was reduced for R553Q and V1293G. Login to comment
49 Mutant V1293G was introduced in a wild type CFTR construct contained in the expression vector pTracer-CMV (15) by a recombinant PCR method. Login to comment
52 V1293G clones were selected and maintained in 800 ␮g/ml Zeocin, and A554E and R553Q constructs were selected and maintained in 1 mg/ml G418. Login to comment
53 Cell Cultures-FRT cells expressing wild type (WT), V1293G, A554E, or R553Q CFTR were cultured on 60-mm Petri dishes with Coon`s modified F12 containing 5% fetal bovine serum, 2 mM L-glutamine, 50 units/ml penicillin, and 50 ␮g/ml streptomycin and selection antibiotics, as described previously (15). Login to comment
85 The apparent dissociation constant of CPTcAMP for mutants V1293G and A554E was not statistically different from that of the wild type protein (Fig. 2). Login to comment
98 Continuous lines (WT, A554E, and V1293G) and broken lines (R553Q) indicate fitting of the data to Equation 1. Login to comment
100 Wild type A554E V1293G R553Q G551D n ϭ 5 n ϭ 4 n ϭ 4 n ϭ 6 n ϭ 7 Imax (␮A/cm2 ) 282.2 Ϯ 13.5 66.9 Ϯ 16.4a 70.2 Ϯ 14a 93.8 Ϯ 19a 10.1 Ϯ 2.8a Kd (␮M) 54.2 Ϯ 11.5 40.5 Ϯ 5.9 48.4 Ϯ 13.5 21.5 Ϯ 4.5a 74.2 Ϯ 12.1 I(20)/I(max) 0.3 Ϯ 0.04 0.34 Ϯ 0.03 0.32 Ϯ 0.05 0.51 Ϯ 0.05a 0.23 Ϯ 0.03 a p Ͻ 0.05. Login to comment
102 It is interesting to note that 20 ␮M CPTcAMP produced a similar current fraction (ϳ0.3) on mutants V1293G and A554E but half of the maximum current (ϳ0.5) on R553Q (see I(20)/ I(max) in Table 1), in agreement with the lower Kd of CPT-cAMP found on this mutant. Login to comment
110 Mutant V1293G behavior was between A554E and R553Q. Login to comment
113 In general, for these compounds Ka changed on mutants in the same direction as Ka for genistein; however, the effect was less marked, except for mutant V1293G, which tended to be more sensitive to Act-06 (see Table 2). Login to comment
127 C-E, comparison of normalized and averaged genistein dose-response relationships of mutants V1293G,A554E,andR553Q(seesymbolkeys)toWT(dashedlines).Eachsymbol is the mean of 4-6 experiments, and vertical bars show S.E. Login to comment
130 Compounds Protein n fA Ka Ki ␮M ␮M Genistein Wild type 5 1.33 Ϯ 0.41 3.08 Ϯ 0.74 562.4 Ϯ 111.1 A554E 6 2.75 Ϯ 0.62 4.58 Ϯ 0.51 408.6 Ϯ 84.8 V1293G 6 4.87 Ϯ 1.91 12 Ϯ 3.9a 270.5 Ϯ 36.4a R553Q 6 1.87 Ϯ 0.12 22.28 Ϯ 5.2a 119.9 Ϯ 34.9a UCCF029 Wild type 4 0.41 Ϯ 0.04 0.021 Ϯ 0.002 1036 Ϯ 523 A554E 4 1.56 Ϯ 0.45a 0.036 Ϯ 0.009 1519 Ϯ 651 V1293G 5 3.19 Ϯ 1.09 0.042 Ϯ 0.008 843 Ϯ 126 R553Q 5 1.08 Ϯ 0.17a 0.154 Ϯ 0.029a 547 Ϯ 99 Act-06 Wild type 5 0.8 Ϯ 0.17 0.69 Ϯ 0.33 439.6 Ϯ 108 A554E 4 1.67 Ϯ 0.42 0.74 Ϯ 0.25 319.1 Ϯ 42.4 V1293G 4 1.25 Ϯ 0.16 0.35 Ϯ 0.09 383.8 Ϯ 28.9 R553Q 6 1.77 Ϯ 0.47a 2.11 Ϯ 0.73 179.1 Ϯ 73.2a a Student`s t test indicated that these values were statistically different from those on WT CFTR with p Ͻ 0.05. Login to comment
150 Mutations of NBDs, like the CF mutation G551D (see Table 1 and Ref. 15) or the other mutations studied here, A554E and V1293G, do not seem to change significantly the sensitivity of the protein to CPTcAMP. Login to comment
159 Conversion of the Ala554 residue to glutamic acid had little effect on the capability of potentiators to favor the conductive state, whereas conversion of Val1293 to glycine increased the Ka for genistein by 4-fold. Login to comment
167 The CFTR proteins are indicated in red, yellow, green, and blue for R553Q, V1293G, A554E and WT, respectively. Login to comment
176 Actually, we found that an increased Ka in R553Q and V1293G with respect to wild type CFTR is accompanied by a reduced Ki (Figs. Login to comment

PMID: 21338920 [PubMed] Sampson HM et al: "Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR."

No. Sentence Comment

152 This hypothesis is consistent with the finding that the G551D and the V1293G mutations alter the affinity of these molecules for CFTR (Moran et al., 2005; Zegarra-Moran et al., 2007). Login to comment