ABCC8 p.Lys1384Arg
| 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, |
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[hide] Potassium channel openers require ATP to bind to a... EMBO J. 1998 Oct 1;17(19):5529-35. Schwanstecher M, Sieverding C, Dorschner H, Gross I, Aguilar-Bryan L, Schwanstecher C, Bryan J
Potassium channel openers require ATP to bind to and act through sulfonylurea receptors.
EMBO J. 1998 Oct 1;17(19):5529-35., [PMID:9755153]
Abstract [show]
KATP channels are composed of a small inwardly rectifying K+ channel subunit, either KIR6.1 or KIR6.2, plus a sulfonylurea receptor, SUR1 or SUR2 (A or B), which belong to the ATP-binding cassette superfamily. SUR1/KIR6.2 reconstitute the neuronal/pancreatic beta-cell channel, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) are proposed to reconstitute the cardiac and the vascular-smooth-muscle-type KATP channels, respectively. We report that potassium channel openers (KCOs) bind to and act through SURs and that binding to SUR1, SUR2A and SUR2B requires ATP. Non-hydrolysable ATP-analogues do not support binding, and Mg2+ or Mn2+ are required. Point mutations in the Walker A motifs or linker regions of both nucleotide-binding folds (NBFs) abolish or weaken [3H]P1075 binding to SUR2B, rendering reconstituted SUR2B/KIR6.2 channels insensitive towards KCOs. The C-terminus of SUR affects KCO affinity with SUR2B approximately SUR1 > SUR2A. KCOs belonging to different structural classes inhibited specific [3H]P1075 binding to SUR2B in a monophasic manner, with the exception of minoxidil sulfate, which induced a biphasic displacement. The affinities of KCO binding to SUR2B were 3.5-8-fold higher than their potencies for activation of SUR2B/KIR6.2 channels. The results establish that SURs are the KCO receptors of KATP channels and suggest that KCO binding requires a conformational change induced by ATP hydrolysis in both NBFs.
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No. Sentence Comment
114 However, by analogy with the results seen with SUR2B, substitution of a lysine for an arginine in either NBF of SUR1 (K719R and/or K1384R) eliminates diazoxide binding and induces a complete loss of activation of SUR1/KIR6.2 channels (results not shown).
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ABCC8 p.Lys1384Arg 9755153:114:131
status: NEW[hide] A novel ABCC8 (SUR1)-dependent mechanism of metabo... J Biol Chem. 2008 Apr 4;283(14):8778-82. Epub 2008 Feb 15. Babenko AP
A novel ABCC8 (SUR1)-dependent mechanism of metabolism-excitation uncoupling.
J Biol Chem. 2008 Apr 4;283(14):8778-82. Epub 2008 Feb 15., [PMID:18281290]
Abstract [show]
ATP/ADP-sensing (sulfonylurea receptor (SUR)/K(IR)6)(4) K(ATP) channels regulate the excitability of our insulin secreting and other vital cells via the differential MgATP/ADP-dependent stimulatory actions of their tissue-specific ATP-binding cassette regulatory subunits (sulfonylurea receptors), which counterbalance the nearly constant inhibitory action of ATP on the K(+) inwardly rectifying pore. Mutations in SUR1 that abolish its stimulation have been found in infants persistently releasing insulin. Activating mutations in SUR1 have been shown to cause neonatal diabetes. Here, analyses of K(IR)6.2-based channels with diabetogenic receptors reveal that MgATP-dependent hyper-stimulation of mutant SUR can compromise the ability of K(ATP) channels to function as metabolic sensors. I demonstrate that the channel hyperactivity rises exponentially with the number of hyperstimulating subunits, so small subpopulations of channels with more than two mutant SUR can dominate hyperpolarizing currents in heterozygous patients. I uncovered an attenuated tolbutamide inhibition of the hyperstimulated mutant, which is normally sensitive to the drug under non-stimulatory conditions. These findings show the key role of SUR in sensing the metabolic index in humans and urge others to (re)test mutant SUR/K(IR)6 channels from probands in physiologic MgATP.
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No. Sentence Comment
80 Second, K719R plus K1384R in the Walker A motifs eliminated the differences between the two channel activities on-cell and in 1 mM MgATP; the fractions of the Pomax were 0.003 Ϯ 0.0012 and 0.0034 Ϯ 0.0018 versus 0.0025 Ϯ 0.001 and 0.0028 Ϯ 0.0011 for NDSUR1K719RϩK1384R versus SUR1K719RϩK1384R channel, respectively (n ϭ 3 for each).
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ABCC8 p.Lys1384Arg 18281290:80:19
status: NEW