ABCC8 p.Glu1305Val
| Predicted by SNAP2: | A: D (80%), C: D (85%), D: D (85%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (85%), N: D (91%), P: D (95%), Q: D (80%), R: D (91%), S: D (85%), T: D (85%), V: D (91%), W: D (91%), Y: D (85%), |
| 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, |
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[hide] Three C-terminal residues from the sulphonylurea r... J Physiol. 2008 Jul 1;586(13):3075-85. Epub 2008 May 1. Dupuis JP, Revilloud J, Moreau CJ, Vivaudou M
Three C-terminal residues from the sulphonylurea receptor contribute to the functional coupling between the K(ATP) channel subunits SUR2A and Kir6.2.
J Physiol. 2008 Jul 1;586(13):3075-85. Epub 2008 May 1., [PMID:18450778]
Abstract [show]
Cardiac ATP-sensitive potassium (K(ATP)) channels are metabolic sensors formed by the association of the inward rectifier potassium channel Kir6.2 and the sulphonylurea receptor SUR2A. SUR2A adjusts channel gating as a function of intracellular ATP and ADP and is the target of pharmaceutical openers and blockers which, respectively, up- and down-regulate Kir6.2. In an effort to understand how effector binding to SUR2A translates into Kir6.2 gating modulation, we examined the role of a 65-residue SUR2A fragment linking transmembrane domain TMD2 and nucleotide-binding domain NBD2 that has been shown to interact with Kir6.2. This fragment of SUR2A was replaced by the equivalent residues of its close homologue, the multidrug resistance protein MRP1. The chimeric construct was expressed in Xenopus oocytes and characterized using the patch-clamp technique. We found that activation by MgADP and synthetic openers was greatly attenuated although apparent affinities were unchanged. Further chimeragenetic and mutagenetic studies showed that mutation of three residues, E1305, I1310 and L1313 (rat numbering), was sufficient to confer this defective phenotype. The same mutations had no effects on channel block by the sulphonylurea glibenclamide or by ATP, suggesting a role for these residues in activatory--but not inhibitory--transduction processes. These results indicate that, within the K(ATP) channel complex, the proximal C-terminal of SUR2A is a critical link between ligand binding to SUR2A and Kir6.2 up-regulation.
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No. Sentence Comment
53 The exact amino acid composition of SUR2A-MRP1 chimeric constructs and mutants were: S1M, SUR2A(M1-V1275) + MRP1(E1262-R1342) + SUR2A(M1358-K1545); S2M, SUR2A(M1-V1275) + MRP1(E1262-L1300) + SUR2A(R1316-K1545); S3M, SUR2A(M1-V1315) + MRP1(R1301-R1342) + SUR2A(M1358-K1545); S4M, SUR2A(M1-V1275) + MRP1(E1262-E1271) + SUR2A(S1286-K1545); S5M, SUR2A(M1-E1285) + MRP1(K1272-P1283) + SUR2A(P1299-K1545); S6M, SUR2A(M1-V1298) + MRP1(P1284-G1291) + SUR2A(E1307-K1545); S7M, SUR2A(M1-Q1304) + MRP1(V1290-L1300) + SUR2A(R1316-K1545); SUR2A(EIL/VFY), SUR2A with mutations E1305V, I1310F and L1313Y; S7M(VFY/EIL), S7M with mutations V1305E, F1310I and Y1313L; SUR2A(EIL/AAA), SUR2A with mutations E1305A, I1310A and L1313A.
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ABCC8 p.Glu1305Val 18450778:53:563
status: NEW