PMID:18198173
| Citation |
Shi, Y, Chen, X, Wu, Z, Shi, W, Yang, Y, Cui, N, Jiang, C and Harrison, RW (2008) cAMP-dependent protein kinase phosphorylation produces interdomain movement in SUR2B leading to activation of the vascular KATP channel. J. Biol. Chem. 283:7523-30 |
|---|---|
| Abstract |
Vascular ATP-sensitive K(+) channels are activated by multiple vasodilating hormones and neurotransmitters via PKA. A critical PKA phosphorylation site (Ser-1387) is found in the second nucleotide-binding domain (NBD(2)) of the SUR2B subunit. To understand how phosphorylation at Ser-1387 leads to changes in channel activity, we modeled the SUR2B using a newly crystallized ABC protein SAV1866. The model showed that Ser-1387 was located on the interface of NBD2 with TMD1 and physically interacted with Tyr-506 in TMD1. A positively charged residue (Arg-1462) in NBD2 was revealed in the close vicinity of Ser-1387. Mutation of either of these three residues abolished PKA-dependent channel activation. Molecular dynamics simulations suggested that Ser-1387, Tyr-506, and Arg-1462 formed a compact triad upon Ser-1387 phosphorylation, leading to reshaping of the NBD2 interface and movements of NBD2 and TMD1. Restriction of the interdomain movements by engineering a disulfide bond between TMD1 and NBD2 prevented the channel activation in a redox-dependent manner. Thus, a channel-gating mechanism is suggested through enhancing the NBD-TMD coupling efficiency following Ser-1387 phosphorylation, which is shared by multiple vasodilators. |
| Links |
PubMed PMC2276326 Online version:10.1074/jbc.M709941200 |
| Keywords |
ATP-Binding Cassette Transporters/chemistry; ATP-Binding Cassette Transporters/genetics; ATP-Binding Cassette Transporters/metabolism; Amino Acid Substitution; Animals; Cyclic AMP-Dependent Protein Kinases/chemistry; Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism; Disulfides/chemistry; Disulfides/metabolism; KATP Channels/chemistry; KATP Channels/genetics; KATP Channels/metabolism; Models, Molecular; Muscle, Smooth, Vascular/chemistry; Muscle, Smooth, Vascular/metabolism; Oxidation-Reduction; Phosphorylation; Potassium Channels/chemistry; Potassium Channels/genetics; Potassium Channels/metabolism; Potassium Channels, Inwardly Rectifying/chemistry; Potassium Channels, Inwardly Rectifying/genetics; Potassium Channels, Inwardly Rectifying/metabolism; Protein Structure, Tertiary/physiology; Rats; Receptors, Drug/chemistry; Receptors, Drug/genetics; Receptors, Drug/metabolism |
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