ABCMdb

ABCC8 p.Ala1184Glu

Predicted by SNAP2:	C: N (61%), D: D (71%), E: D (71%), F: D (59%), G: N (57%), H: D (63%), I: N (53%), K: D (63%), L: D (53%), M: N (57%), N: N (53%), P: D (71%), Q: D (59%), R: D (59%), S: N (97%), T: N (93%), V: D (53%), W: D (71%), Y: D (66%),
Predicted by PROVEAN:	C: N, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: N, V: N, W: D, Y: D,

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[hide] Two neonatal diabetes mutations on transmembrane h... J Biol Chem. 2012 May 25;287(22):17985-95. doi: 10.1074/jbc.M112.349019. Epub 2012 Mar 27. Ortiz D, Voyvodic P, Gossack L, Quast U, Bryan J
Two neonatal diabetes mutations on transmembrane helix 15 of SUR1 increase affinity for ATP and ADP at nucleotide binding domain 2.
J Biol Chem. 2012 May 25;287(22):17985-95. doi: 10.1074/jbc.M112.349019. Epub 2012 Mar 27., [PMID:22451668]

Abstract [show]
K(ATP) channels, (SUR1/Kir6.2)(4) (sulfonylurea receptor type 1/potassium inward rectifier type 6.2) respond to the metabolic state of pancreatic beta-cells, modulating membrane potential and insulin exocytosis. Mutations in both subunits cause neonatal diabetes by overactivating the pore. Hyperactive channels fail to close appropriately with increased glucose metabolism; thus, beta-cell hyperpolarization limits insulin release. K(ATP) channels are inhibited by ATP binding to the Kir6.2 pore and stimulated, via an uncertain mechanism, by magnesium nucleotides at SUR1. Glibenclamide (GBC), a sulfonylurea, was used as a conformational probe to compare nucleotide action on wild type versus Q1178R and R1182Q SUR1 mutants. GBC binds with high affinity to aporeceptors, presumably in the inward facing ATP-binding cassette configuration; MgATP reduces binding affinity via a shift to the outward facing conformation. To determine nucleotide affinities under equilibrium, non-hydrolytic conditions, Mg(2+) was eliminated. A four-state equilibrium model describes the allosteric linkage. The K(D) for ATP(4-) is ~1 versus 12 mM, Q1178R versus wild type, respectively. The linkage constant is ~10, implying that outward facing conformations bind GBC with a lower affinity, 9-10 nM for Q1178R. Thus, nucleotides cannot completely inhibit GBC binding. Binding of channel openers is reported to require ATP hydrolysis, but diazoxide, a SUR1-selective agonist, concentration-dependently augments ATP(4-) action. An eight-state model describes linkage between diazoxide and ATP(4-) binding; diazoxide markedly increases the affinity of Q1178R for ATP(4-) and ATP(4-) augments diazoxide binding. NBD2, but not NBD1, has a higher affinity for ATP (and ADP) in mutant versus wild type (with or without Mg(2+)). Thus, the mutants spend more time in nucleotide-bound conformations, with reduced affinity for GBC, that activate the pore.

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No. Sentence Comment
48 These substitutions are in a cluster of mutations that cause either neonatal diabetes (Q1178R, R1182Q, and A1184E) or hyperinsulinism (C1174F and S1185A). Login to comment