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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

^* This work was supported in part by National Institutes of Health Grant HL067890 (to C. J.) and the Georgia State University Research Program Enhancement Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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.

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