ABCC8 p.Cys1174Phe
| ClinVar: |
c.3520G>A
,
p.Val1174Met
D
, Likely pathogenic
|
| Predicted by SNAP2: | A: N (57%), D: D (80%), E: D (80%), F: N (78%), G: D (75%), H: D (75%), I: D (63%), K: D (80%), L: D (63%), M: D (63%), N: D (66%), P: D (80%), Q: D (75%), R: D (80%), S: D (63%), T: D (71%), V: D (63%), W: D (71%), Y: N (82%), |
| Predicted by PROVEAN: | A: N, D: D, E: D, F: N, G: D, H: N, I: N, K: D, L: N, M: N, N: D, P: D, Q: N, R: D, S: N, T: N, V: N, W: N, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Identification of the high-affinity tolbutamide si... Diabetes. 1999 Jun;48(6):1341-7. Ashfield R, Gribble FM, Ashcroft SJ, Ashcroft FM
Identification of the high-affinity tolbutamide site on the SUR1 subunit of the K(ATP) channel.
Diabetes. 1999 Jun;48(6):1341-7., [PMID:10342826]
Abstract [show]
ATP-sensitive potassium channels (K(ATP)) are formed from four pore-forming Kir6.2 subunits complexed with four regulatory sulfonylurea receptor subunits (SUR1 in pancreatic beta-cells, SUR2A in heart). The sensitivity of the channel to different sulfonylureas depends on the SUR isoform. In particular, Kir6.2-SUR1 but not Kir6.2-SUR2A channels are blocked by tolbutamide with high affinity. We made chimeras between SUR1 and SUR2A to identify the region of the protein involved in high-affinity tolbutamide block. Chimeric SURs were coexpressed with Kir6.2 in Xenopus oocytes, and macroscopic currents were measured in inside-out membrane patches. High-affinity tolbutamide inhibition could be conferred on SUR2A by replacing transmembrane domains (TMs) 14-16 with the corresponding region of SUR1. Conversely, high-affinity tolbutamide inhibition of SUR1 was abolished by replacing TMs 13-16 with the corresponding SUR2A sequence, or by mutating a single serine residue within this region to tyrosine (S1237Y). Binding of [3H]glibenclamide to membranes expressing SUR1 was abolished concomitantly with the loss of high-affinity tolbutamide block. These results suggest that a site in the COOH-terminal set of TMs of the SUR1 subunit of the K(ATP) channel is involved in the binding of tolbutamide and glibenclamide.
Comments [show]
None has been submitted yet.
No. Sentence Comment
127 Most mutations did not affect tolbutamide sensitivity: these included C1128T, T1130I, C1141S, C1174F, Q1190E, S1201C, A1204S, Y1218H, Q1223K, Y1229L, L1226M (data not shown; n = 2-4 patches in each case).
X
ABCC8 p.Cys1174Phe 10342826:127:94
status: NEW[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.
Comments [show]
None has been submitted yet.
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).
X
ABCC8 p.Cys1174Phe 22451668:48:135
status: NEW139 E, neonatal diabetes (Q1178R in red and R1182Q in green) and hyperinsulinemia (C1174F in blue) causing mutations are clustered on transmembrane helix 15 (yellow), which feeds into NBD1 (light gray).
X
ABCC8 p.Cys1174Phe 22451668:139:79
status: NEW[hide] Neonatal Diabetes and Congenital Hyperinsulinism C... Front Endocrinol (Lausanne). 2015 Apr 15;6:48. doi: 10.3389/fendo.2015.00048. eCollection 2015. Ortiz D, Bryan J
Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP.
Front Endocrinol (Lausanne). 2015 Apr 15;6:48. doi: 10.3389/fendo.2015.00048. eCollection 2015., [PMID:25926814]
Abstract [show]
ATP-sensitive K(+) (KATP) channels composed of potassium inward-rectifier type 6.2 and sulfonylurea receptor type 1 subunits (Kir6.2/SUR1)4 are expressed in various cells in the brain and endocrine pancreas where they couple metabolic status to membrane potential. In beta-cells, increases in cytosolic [ATP/ADP]c inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively. SUR1 is reported to be a Mg(2+)-dependent ATPase. A prevailing model posits that ATP hydrolysis at SUR1 is required to stimulate openings of the pore. However, recent work shows nucleotide binding, without hydrolysis, is sufficient to switch SUR1 to stimulatory conformations. The actions of nucleotides, ATP and ADP, on ND (SUR1E1506D) and CHI (SUR1E1506K) mutants, without Kir6.2, were compared to assess both models. Both substitutions significantly impair hydrolysis in SUR1 homologs. SUR1E1506D has greater affinity for MgATP than wildtype; SUR1E1506K has reduced affinity. Without Mg(2+), SUR1E1506K has a greater affinity for ATP(4-) consistent with electrostatic attraction between ATP(4-), unshielded by Mg(2+), and the basic lysine. Further analysis of ND and CHI ABCC8 mutants in the second transmembrane and nucleotide-binding domains (TMD2 and NBD2) found a relation between their affinities for ATP (+/-Mg(2+)) and their clinical phenotype. Increased affinity for ATP is associated with ND; decreased affinity with CHI. In contrast, MgADP showed a weaker relationship. Diazoxide, known to reduce insulin release in some CHI cases, potentiates switching of CHI mutants from non-stimulatory to stimulatory states consistent with diazoxide stabilizing a nucleotide-bound conformation. The results emphasize the greater importance of nucleotide binding vs. hydrolysis in the regulation of KATP channels in vivo.
Comments [show]
None has been submitted yet.
No. Sentence Comment
122 to the current regulatory model, both E1506 substitutions have reduced affinity for MgADP (Figure 4), consistent with electrophysiological data demonstrating that SUR1E1506D/Kir6.2 and 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0.0 0.2 0.4 0.6 0.8 1.0 E1506Q Q1178R E1506D R1182Q I1424V WT S1185A C1174F E1506K G1479R Specific Bound GBC [MgATP] (&#b5;M) 10 -1 10 0 10 1 10 2 10 3 10 4 10 5 0.0 0.2 0.4 0.6 0.8 1.0 E1506Q E1506K Q1178R I1424V E1506D R1182Q WT S1185A C1174F G1479R Specific Bound GBC [ATP 4- ] (&#b5;M) B A FIGURE 3 | Comparison of nucleotide-induced conformational switching in WT and SUR1 mutants.
X
ABCC8 p.Cys1174Phe 25926814:122:290
status: NEWX
ABCC8 p.Cys1174Phe 25926814:122:459
status: NEW128 To support this hypothesis we analyzed additional mutations including I1424V (ND) and G1479R (CHI) in NBD2 and a cluster of disease causing mutations in TMD2: C1174F (CHI), S1185A (CHI), Q1178R (ND), and R1182Q (ND).
X
ABCC8 p.Cys1174Phe 25926814:128:159
status: NEW151 Figure 5 shows that diazoxide potentiates the 1 10 100 1000 0.0 0.2 0.4 0.6 0.8 1.0 Q1178R I1424V R1182Q S1185A C1174F WT E1506Q E1506D G1479R E1506K Specific Bound GBC [MgADP] (&#b5;M) FIGURE 4 | MgADP-induced conformational switching in WT and SUR1 mutants.
X
ABCC8 p.Cys1174Phe 25926814:151:112
status: NEW152 10 100 1 0.0 0.2 0.4 0.6 0.8 1.0 1 10 100 0.0 0.2 0.4 0.6 0.8 1.0 WT S1185A C1174F G1479R Specific Bound GBC [Diazoxide] (&#b5;M) Specific Bound GBC [Diazoxide] (&#b5;'c;) FIGURE 5 | Diazoxide potentiates conformational switching in WT and CHI SUR1 mutants.
X
ABCC8 p.Cys1174Phe 25926814:152:76
status: NEW