ABCC8 p.Lys1384Ala
| Predicted by SNAP2: | A: D (91%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (91%), I: D (91%), L: D (95%), M: D (91%), N: D (95%), P: D (95%), Q: D (91%), R: D (80%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
117 In NBD2, K1348M (SUR2B) and K1384A (SUR1) reduced ADP binding [81].
X
ABCC8 p.Lys1384Ala 16442101:117:28
status: NEW[hide] C-terminal tails of sulfonylurea receptors control... Circ Res. 2000 Nov 10;87(10):873-80. Matsuoka T, Matsushita K, Katayama Y, Fujita A, Inageda K, Tanemoto M, Inanobe A, Yamashita S, Matsuzawa Y, Kurachi Y
C-terminal tails of sulfonylurea receptors control ADP-induced activation and diazoxide modulation of ATP-sensitive K(+) channels.
Circ Res. 2000 Nov 10;87(10):873-80., [PMID:11073882]
Abstract [show]
The ATP-sensitive K(+) (K(ATP)) channels are composed of the pore-forming K(+) channel Kir6.0 and different sulfonylurea receptors (SURs). SUR1, SUR2A, and SUR2B are sulfonylurea receptors that are characteristic for pancreatic, cardiac, and vascular smooth muscle-type K(ATP) channels, respectively. The structural elements of SURs that are responsible for their different characteristics have not been entirely determined. Here we report that the 42 amino acid segment at the C-terminal tail of SURs plays a critical role in the differential activation of different SUR-K(ATP) channels by ADP and diazoxide. In inside-out patches of human embryonic kidney 293T cells coexpressing distinct SURs and Kir6.2, much higher concentrations of ADP were needed to activate channels that contained SUR2A than SUR1 or SUR2B. In all types of K(ATP) channels, diazoxide increased potency but not efficacy of ADP to evoke channel activation. Replacement of the C-terminal segment of SUR1 with that of SUR2A inhibited ADP-mediated channel activation and reduced diazoxide modulation. Point mutations of the second nucleotide-binding domains (NBD2) of SUR1 and SUR2B, which would prevent ADP binding or ATP hydrolysis, showed similar effects. It is therefore suggested that the C-terminal segment of SUR2A possesses an inhibitory effect on NBD2-mediated ADP-induced channel activation, which underlies the differential effects of ADP and diazoxide on K(ATP) channels containing different SURs.
Comments [show]
None has been submitted yet.
No. Sentence Comment
106 Effects of Mutations in NBD2 of SUR2B and SUR1 on the ADP and Diazoxide Action Like other ATP-binding cassette proteins, SURs possess 2 nucleotide-binding domains (NBD1 and NBD2, respectively).3 It was shown that SUR1 binds ATP at NBD1 and ADP at NBD2.24 The NBDs possess the Walker A and B motifs to form a portion of a nucleotide-binding pocket.25 In various ATP-binding proteins, Walker A motif in NBDs is responsible for binding or hydrolysis of nucleotides, where the highly conserved lysine residue plays a critical role.26-28 The mutation of this lysine residue in NBD2 extinguishes the ADP-mediated activation of SUR1 and SUR2A-KATP channels.19,21,29 Therefore, we introduced mutations of the lysine residue in NBD2 of SUR2B and SUR1 (K1348M in SUR2B and K1384A in SUR1) and examined the effects of ADP and diazoxide on the mutant SUR/ Kir6.2 channels (Figure 3).
X
ABCC8 p.Lys1384Ala 11073882:106:763
status: NEW110 The mutant SUR1(K1384A)/Kir6.2 channel also scarcely responded to ADP (Figure 3B).
X
ABCC8 p.Lys1384Ala 11073882:110:16
status: NEW111 Different from the SUR2B mutant, diazoxide (30 and 300 mol/L) enhanced the SUR1(K1384A)/ Kir6.2 channel to Ϸ0.1 and Ϸ0.2 in rNPo, respectively, irrespective of [ADP].
X
ABCC8 p.Lys1384Ala 11073882:111:88
status: NEW114 Effects of intracellular ADP, diazoxide, and pinacidil on SUR2B(K1348M)/ Kir6.2 (A) and SUR1(K1384A)/Kir6.2 (B) channels. Left, Effects of ADP and diazoxide (DZX) or pinacidil (PIN) on SUR2(K1348M)/Kir6.2 and SUR1(K1384A)/ Kir6.2 channels. ATP, ADP, and diazoxide were added to the bath solution as indicated by bars. Right, Relationship between the concentration of ADP and relative NPo (rNPo) in the absence (⅜) and presence of diazoxide (U, 30 mol/L and ⅷ, 300 mol/L) or pinacidil (ᮀ, 100 mol/L).
X
ABCC8 p.Lys1384Ala 11073882:114:93
status: NEWX
ABCC8 p.Lys1384Ala 11073882:114:214
status: NEW135 In the chimera SUR1-2A/Kir6.2 and the mutant SUR1(K1384A)/Kir6.2 channels, the ADP-dependent component was largely attenuated, and diazoxide (300 mol/L) increased the channel rNPo by Ϸ0.2 irrespective of [ADP].
X
ABCC8 p.Lys1384Ala 11073882:135:50
status: NEW97 Effects of Mutations in NBD2 of SUR2B and SUR1 on the ADP and Diazoxide Action Like other ATP-binding cassette proteins, SURs possess 2 nucleotide-binding domains (NBD1 and NBD2, respectively).3 It was shown that SUR1 binds ATP at NBD1 and ADP at NBD2.24 The NBDs possess the Walker A and B motifs to form a portion of a nucleotide-binding pocket.25 In various ATP-binding proteins, Walker A motif in NBDs is responsible for binding or hydrolysis of nucleotides, where the highly conserved lysine residue plays a critical role.26-28 The mutation of this lysine residue in NBD2 extinguishes the ADP-mediated activation of SUR1 and SUR2A-KATP channels.19,21,29 Therefore, we introduced mutations of the lysine residue in NBD2 of SUR2B and SUR1 (K1348M in SUR2B and K1384A in SUR1) and examined the effects of ADP and diazoxide on the mutant SUR/ Kir6.2 channels (Figure 3).
X
ABCC8 p.Lys1384Ala 11073882:97:763
status: NEW101 The mutant SUR1(K1384A)/Kir6.2 channel also scarcely responded to ADP (Figure 3B).
X
ABCC8 p.Lys1384Ala 11073882:101:16
status: NEWX
ABCC8 p.Lys1384Ala 11073882:101:87
status: NEW102 Different from the SUR2B mutant, diazoxide (30 and 300 òe;mol/L) enhanced the SUR1(K1384A)/ Kir6.2 channel to b07;0.1 and b07;0.2 in rNPo, respectively, irrespective of [ADP].
X
ABCC8 p.Lys1384Ala 11073882:102:87
status: NEW105 Effects of intracellular ADP, diazoxide, and pinacidil on SUR2B(K1348M)/ Kir6.2 (A) and SUR1(K1384A)/Kir6.2 (B) channels. Left, Effects of ADP and diazoxide (DZX) or pinacidil (PIN) on SUR2(K1348M)/Kir6.2 and SUR1(K1384A)/ Kir6.2 channels. ATP, ADP, and diazoxide were added to the bath solution as indicated by bars. Right, Relationship between the concentration of ADP and relative NPo (rNPo) in the absence (Ǧc;) and presence of diazoxide (U, 30 òe;mol/L and , 300 òe;mol/L) or pinacidil (Ⴢ, 100 òe;mol/L).
X
ABCC8 p.Lys1384Ala 11073882:105:93
status: NEWX
ABCC8 p.Lys1384Ala 11073882:105:214
status: NEW126 In the chimera SUR1-2A/Kir6.2 and the mutant SUR1(K1384A)/Kir6.2 channels, the ADP-dependent component was largely attenuated, and diazoxide (300 òe;mol/L) increased the channel rNPo by b07;0.2 irrespective of [ADP].
X
ABCC8 p.Lys1384Ala 11073882:126:50
status: NEW96 Effects of Mutations in NBD2 of SUR2B and SUR1 on the ADP and Diazoxide Action Like other ATP-binding cassette proteins, SURs possess 2 nucleotide-binding domains (NBD1 and NBD2, respectively).3 It was shown that SUR1 binds ATP at NBD1 and ADP at NBD2.24 The NBDs possess the Walker A and B motifs to form a portion of a nucleotide-binding pocket.25 In various ATP-binding proteins, Walker A motif in NBDs is responsible for binding or hydrolysis of nucleotides, where the highly conserved lysine residue plays a critical role.26-28 The mutation of this lysine residue in NBD2 extinguishes the ADP-mediated activation of SUR1 and SUR2A-KATP channels.19,21,29 Therefore, we introduced mutations of the lysine residue in NBD2 of SUR2B and SUR1 (K1348M in SUR2B and K1384A in SUR1) and examined the effects of ADP and diazoxide on the mutant SUR/ Kir6.2 channels (Figure 3).
X
ABCC8 p.Lys1384Ala 11073882:96:763
status: NEW100 The mutant SUR1(K1384A)/Kir6.2 channel also scarcely responded to ADP (Figure 3B).
X
ABCC8 p.Lys1384Ala 11073882:100:16
status: NEW104 Effects of intracellular ADP, diazoxide, and pinacidil on SUR2B(K1348M)/ Kir6.2 (A) and SUR1(K1384A)/Kir6.2 (B) channels. Left, Effects of ADP and diazoxide (DZX) or pinacidil (PIN) on SUR2(K1348M)/Kir6.2 and SUR1(K1384A)/ Kir6.2 channels. ATP, ADP, and diazoxide were added to the bath solution as indicated by bars. Right, Relationship between the concentration of ADP and relative NPo (rNPo) in the absence (Ǧc;) and presence of diazoxide (U, 30 òe;mol/L and , 300 òe;mol/L) or pinacidil (Ⴢ, 100 òe;mol/L).
X
ABCC8 p.Lys1384Ala 11073882:104:93
status: NEWX
ABCC8 p.Lys1384Ala 11073882:104:214
status: NEW125 In the chimera SUR1-2A/Kir6.2 and the mutant SUR1(K1384A)/Kir6.2 channels, the ADP-dependent component was largely attenuated, and diazoxide (300 òe;mol/L) increased the channel rNPo by b07;0.2 irrespective of [ADP].
X
ABCC8 p.Lys1384Ala 11073882:125:50
status: NEW[hide] Nateglinide, a D-phenylalanine derivative lacking ... J Pharmacol Exp Ther. 2003 Mar;304(3):1025-32. Chachin M, Yamada M, Fujita A, Matsuoka T, Matsushita K, Kurachi Y
Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels.
J Pharmacol Exp Ther. 2003 Mar;304(3):1025-32., [PMID:12604678]
Abstract [show]
A novel antidiabetic agent, nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
Comments [show]
None has been submitted yet.
No. Sentence Comment
8 This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP.
X
ABCC8 p.Lys1384Ala 12604678:8:143
status: NEW36 SUR1 whose serine at position 1237 was substituted with tyrosine [SUR1(S1237Y)], SUR1 whose lysine at position 1384 was substituted with alanine [SUR1(K1384A)], and Kir6.2 whose lysine at position 185 was substituted with glutamine [Kir6.2(K185Q)] were constructed using the GeneEditor in vitro site-directed mutagenesis system (Promega, Madison, WI).
X
ABCC8 p.Lys1384Ala 12604678:36:151
status: NEW147 To test this hypothesis, we used SUR1 where lysine 1384 in the Walker A motif in nucleotide binding domain 2 was substituted with alanine [SUR1(K1384A)] (Fig. 4C).
X
ABCC8 p.Lys1384Ala 12604678:147:144
status: NEW149 MgADP (100 M) inhibited SUR1(K1384A)/Kir6.2 channels by 58.2 ee; 8.6 and 69.7 Ϯ 5.2% in the absence and presence of nateglinide (10 M), re-Fig. 4.
X
ABCC8 p.Lys1384Ala 12604678:149:37
status: NEWX
ABCC8 p.Lys1384Ala 12604678:149:67
status: NEW150 Effect of nateglinide on SUR1/Kir6.2(K185Q), SUR1/Kir6.2, and SUR1(K1384A)/Kir6.2 channels in the presence and absence of nucleotides.
X
ABCC8 p.Lys1384Ala 12604678:150:67
status: NEWX
ABCC8 p.Lys1384Ala 12604678:150:76
status: NEW151 Effects of nateglinide on SUR1/Kir6.2(K185Q) (A), SUR1/Kir6.2 (B), and SUR1(K1384A)/Kir6.2 (C) channel currents were measured in inside-out patches.
X
ABCC8 p.Lys1384Ala 12604678:151:76
status: NEW157 Nateglinide inhibited SUR1(K1384A)/Kir6.2 channel currents by 60.5 Ϯ 6.3 and 71.2 Ϯ 3.8% in the absence and presence of MgADP, respectively (Fig. 4D).
X
ABCC8 p.Lys1384Ala 12604678:157:27
status: NEW146 To test this hypothesis, we used SUR1 where lysine 1384 in the Walker A motif in nucleotide binding domain 2 was substituted with alanine [SUR1(K1384A)] (Fig. 4C).
X
ABCC8 p.Lys1384Ala 12604678:146:144
status: NEW148 MgADP (100 òe;M) inhibited SUR1(K1384A)/Kir6.2 channels by 58.2 afe; 8.6 and 69.7 afe; 5.2% in the absence and presence of nateglinide (10 òe;M), re- Fig. 4.
X
ABCC8 p.Lys1384Ala 12604678:148:36
status: NEW156 Nateglinide inhibited SUR1(K1384A)/Kir6.2 channel currents by 60.5 afe; 6.3 and 71.2 afe; 3.8% in the absence and presence of MgADP, respectively (Fig. 4D).
X
ABCC8 p.Lys1384Ala 12604678:156:27
status: NEW