ABCMdb

ABCC8 p.Glu1506Gln

Predicted by SNAP2:	A: D (91%), C: D (91%), D: D (91%), F: D (91%), G: D (95%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (91%), P: D (85%), Q: D (85%), R: D (95%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, F: D, G: D, H: D, I: D, K: 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.

Publications
[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.

Sentences [show]
No. Sentence Comment
119 10-2 10-1 100 101 102 103 104 105 0.0 0.2 0.4 0.6 0.8 1.0 WT E1506D E1506K E1506Q 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 WT E1506K E1506D E1506Q Specific Bound GBC [ATP 4- ] (&#b5;M) B A C FIGURE 2 | (A) Representation of NBD2 based on Sav1866. Login to 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. Login to comment
126 The neutral E1506Q substitution leads to a similar reduction in MgADP affinity (8). Login to comment
151 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. Login to comment
170 It is notable that the E1506D, and particularly the E1506Q, substitutions with higher affinities for ATP are not switched appropriately by endogenously generated ATP. Login to comment