ABCC7 p.Gln493Ala
| ClinVar: |
c.1478A>C
,
p.Gln493Pro
?
, not provided
c.1478A>G , p.Gln493Arg ? , not provided c.1477C>T , p.Gln493* D , Pathogenic |
| CF databases: |
c.1477C>T
,
p.Gln493*
D
, CF-causing
c.1478A>C , p.Gln493Pro (CFTR1) D , c.1478A>G , p.Gln493Arg (CFTR1) ? , This mutation was identified by DGGE and direct sequencing which was found in a Bulgarian CF chromosome. |
| Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (91%), E: D (85%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (85%), N: D (85%), P: D (95%), R: D (91%), S: D (85%), T: D (85%), V: D (85%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Insight in eukaryotic ABC transporter function by ... FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19. Frelet A, Klein M
Insight in eukaryotic ABC transporter function by mutation analysis.
FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19., 2006-02-13 [PMID:16442101]
Abstract [show]
With regard to structure-function relations of ATP-binding cassette (ABC) transporters several intriguing questions are in the spotlight of active research: Why do functional ABC transporters possess two ATP binding and hydrolysis domains together with two ABC signatures and to what extent are the individual nucleotide-binding domains independent or interacting? Where is the substrate-binding site and how is ATP hydrolysis functionally coupled to the transport process itself? Although much progress has been made in the elucidation of the three-dimensional structures of ABC transporters in the last years by several crystallographic studies including novel models for the nucleotide hydrolysis and translocation catalysis, site-directed mutagenesis as well as the identification of natural mutations is still a major tool to evaluate effects of individual amino acids on the overall function of ABC transporters. Apart from alterations in characteristic sequence such as Walker A, Walker B and the ABC signature other parts of ABC proteins were subject to detailed mutagenesis studies including the substrate-binding site or the regulatory domain of CFTR. In this review, we will give a detailed overview of the mutation analysis reported for selected ABC transporters of the ABCB and ABCC subfamilies, namely HsCFTR/ABCC7, HsSUR/ABCC8,9, HsMRP1/ABCC1, HsMRP2/ABCC2, ScYCF1 and P-glycoprotein (Pgp)/MDR1/ABCB1 and their effects on the function of each protein.
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None has been submitted yet.
No. Sentence Comment
299 [137] Q493A, Q1291A, N505C, N1303K Q493A and N505C reduced and increased the frequency of CO, respectively.
X
ABCC7 p.Gln493Ala 16442101:299:6
status: NEWX
ABCC7 p.Gln493Ala 16442101:299:35
status: NEW[hide] Mutations that change the position of the putative... J Biol Chem. 2002 Jan 18;277(3):2125-31. Berger AL, Ikuma M, Hunt JF, Thomas PJ, Welsh MJ
Mutations that change the position of the putative gamma-phosphate linker in the nucleotide binding domains of CFTR alter channel gating.
J Biol Chem. 2002 Jan 18;277(3):2125-31., 2002-01-18 [PMID:11788611]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is an ATP-binding cassette transporter that contains conserved nucleotide-binding domains (NBDs). In CFTR, the NBDs bind and hydrolyze ATP to open and close the channel. Crystal structures of related NBDs suggest a structural model with an important signaling role for a gamma-phosphate linker peptide that couples bound nucleotide to movement of an alpha-helical subdomain. We mutated two residues in CFTR that the structural model predicts will uncouple effects of nucleotide binding from movement of the alpha-helical subdomain. These residues are Gln-493 and Gln-1291, which may directly connect the ATP gamma-phosphate to the gamma-phosphate linker, and residues Asn-505 and Asn-1303, which may form hydrogen bonds that stabilize the linker. In NBD1, Q493A reduced the frequency of channel opening, suggesting a role for this residue in coupling ATP binding to channel opening. In contrast, N505C increased the frequency of channel opening, consistent with a role for Asn-505 in stabilizing the inactive state of the NBD. In NBD2, Q1291A decreased the effects of pyrophosphate without altering other functions. Mutations of Asn-1303 decreased the rate of channel opening and closing, suggesting an important role for NBD2 in controlling channel burst duration. These findings are consistent with both the bacterial NBD structural model and gating models for CFTR. Our results extend models of nucleotide-induced structural changes from bacterial NBDs to a functional mammalian ATP-binding cassette transporter.
Comments [show]
None has been submitted yet.
No. Sentence Comment
4 In NBD1, Q493A reduced the frequency of channel opening, suggesting a role for this residue in coupling ATP binding to channel opening.
X
ABCC7 p.Gln493Ala 11788611:4:9
status: NEW79 Single-channel gating of wild type CFTR, CFTR-Q493A, and CFTR-Q1291A.
X
ABCC7 p.Gln493Ala 11788611:79:46
status: NEW80 A, examples of current from excised inside-out membrane patches containing single CFTR channels in the presence of 1 mM ATP and 75 nM PKA. Membrane potential was clamped at -80 mV. B, data from multiple patches. Asterisk indicates p Ͻ 0.05; n ϭ 7 for WT, n ϭ 4 for CFTR-Q493A, and n ϭ 3 for CFTR-Q1291A.
X
ABCC7 p.Gln493Ala 11788611:80:288
status: NEW93 In contrast, the Q493A variant exhibited a substantially reduced Po because of a prolonged interburst interval with little change in FIG. 3.
X
ABCC7 p.Gln493Ala 11788611:93:17
status: NEW94 Wild type CFTR, CFTR-Q493A, and CFTR-Q1291A had similar dose response curves for ATP-stimulated Cl- current.
X
ABCC7 p.Gln493Ala 11788611:94:21
status: NEW98 The apparent EC50 was 176 Ϯ 67 M for wild type CFTR, 217 Ϯ 55 M for CFTR-Q493A, and 159 Ϯ 70 M for CFTR-Q1291A.
X
ABCC7 p.Gln493Ala 11788611:98:101
status: NEW101 Wild type CFTR, CFTR-Q493A, and CFTR-Q1291A showed similar cation requirements for Cl-channel activity.
X
ABCC7 p.Gln493Ala 11788611:101:21
status: NEW112 Because ATP binding may open the CFTR Cl-channel (13, 14), thereby reducing the interburst interval, we asked if the prolonged interburst interval in Q493A was consistent with attenuated binding.
X
ABCC7 p.Gln493Ala 11788611:112:150
status: NEW114 Wild type CFTR and CFTR-Q493A had the same apparent EC50 for ATP (Fig. 3).
X
ABCC7 p.Gln493Ala 11788611:114:24
status: NEW121 Wild type CFTR, CFTR-Q493A, and CFTR-Q1291A were all inhibited by ADP.
X
ABCC7 p.Gln493Ala 11788611:121:21
status: NEW122 A, examples of patches incubated with ATP (1 mM) and ADP (1 mM) during the times indicated. B, data from multiple patches show that wild type CFTR, CFTR-Q493A, and CFTR-Q1291A currents were inhibited by ADP to a similar extent.
X
ABCC7 p.Gln493Ala 11788611:122:153
status: NEW127 The membrane potential was clamped at -40 mV. Patches were incubated with 1 mM ATP and 4 mM PPi during the times indicated. B, data from multiple patches show that 4 mM PPi stimulated less Cl- current in CFTR-Q1291A (n ϭ 6) than in wild type CFTR (n ϭ 4) or CFTR-Q493A (n ϭ 4).
X
ABCC7 p.Gln493Ala 11788611:127:275
status: NEW130 Fig. 4 shows that varying the divalent cation generated similar effects for wild type CFTR and the Q493A variant.
X
ABCC7 p.Gln493Ala 11788611:130:99
status: NEW134 The Q493A mutation did not alter the response to either agent (Figs.
X
ABCC7 p.Gln493Ala 11788611:134:4
status: NEW136 Mutating Asn-505 in NBD1 Can Increase Channel Opening-The N505C mutation had an effect opposite to that of Q493A; it reduced the interburst interval and increased Po (Fig. 7).
X
ABCC7 p.Gln493Ala 11788611:136:107
status: NEW137 As with Q493A, burst duration did not change.
X
ABCC7 p.Gln493Ala 11788611:137:8
status: NEW141 The opposite effects of the Q493A and N505C mutations on gating are consistent with the expectation that these mutations might have different effects on the ␥-phosphate linker.
X
ABCC7 p.Gln493Ala 11788611:141:28
status: NEW