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J. Biol. Chem., Vol. 283, Issue 12, 7523-7530, March 21, 2008

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cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular K_ATP Channel^*

Yun Shi¹, Xianfeng Chen¹, Zhongying Wu, Weiwei Shi, Yang Yang, Ningren Cui, Chun Jiang², and Robert W. Harrison³

From the Departments of Biology and Computer Science, Georgia State University, Atlanta, Georgia 30302-4010

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 (NBD₂) 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.

Received for publication, December 5, 2007

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 404-413-5404; Fax: 404-413-5301; E-mail: cjiang{at}gsu.edu. ³ To whom correspondence may be addressed. Tel.: 404-413-5724; Fax: 404-413-5717; E-mail: rharrison{at}cs.gsu.edu.