SUR domains that associate with and gate KATP pores define a novel gatekeeper
SUR domains that associate with and gate KATP pores define a novel gatekeeper
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DOI：
10.1074/jbc.c300363200
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发表时间：
2003-10-24
影响因子：
4.8
通讯作者：
Bryan, J
中科院分区：
文献类型：
--
作者：
Babenko, AP;Bryan, J
K+通道的结构-功能分析确定了一种常见的孔结构，其门控取决于不同的信号传感元件。K-ATP通道的长的、ATP抑制的K（IR）6.0孔的“守门人”是ABC蛋白、SURs、通道开放和关闭药物的受体。SUR/K-IR耦合存在几种竞争模型。我们发现，SUR TMD 0，N-末端束的五个跨膜螺旋，特别是与K（IR）6.2，迫使几乎沉默的孔爆裂像天然KATP通道和增强表面表达。包含L0的相邻亚膜残基，TMD 0和刺激性核苷酸和药物结合ABC核心之间的接头，产生组成型活性通道，而额外的细胞质残基抵消这种激活，建立完整孔的平均开放和爆裂时间之间的关系。缺乏TMD 0的SUR片段不能调节K-IR。因此TMD 0是将SUR锚定到K-IR孔的结构域。与嵌合ABCC/K（IR）s和模型通道结构的数据一致，我们提出TMD 0-L0与K-IR的外螺旋和N末端的相互作用双向调节门控。这些结果解释并预测了与簇集的ABCC 8（9）/KCNJ 11（8）基因的5'端改变相关的病理。
Structure-function analyses of K+ channels identify a common pore architecture whose gating depends on diverse signal sensing elements. The "gatekeepers" of the long, ATP-inhibited K(IR)6.0 pores of K-ATP channels are ABC proteins, SURs, receptors for channel opening and closing drugs. Several competing models for SUR/K-IR coupling exist. We show that SUR TMD0, the N-terminal bundle of five transmembrane helices, specifically associates with K(IR)6.2, forcing nearly silent pores to burst like native KATP channels and enhancing surface expression. Inclusion of adjacent submembrane residues of L0, the linker between TMD0 and the stimulatory nucleotide- and drug-binding ABC core, generates constitutively active channels, whereas additional cytoplasmic residues counterbalance this activation establishing a relationship between the mean open and burst times of intact pores. SUR fragments, lacking TMD0, fail to modulate K-IR. TMD0 is thus the domain that anchors SUR to the K-IR pore. Consistent with data on chimeric ABCC/K(IR)s and a modeled channel structure, we propose that interactions of TMD0-L0 with the outer helix and N terminus of K-IR bidirectionally modulate gating. The results explain and predict pathologies associated with alteration of the 5' ends of clustered ABCC8 (9)/KCNJ11 (8) genes.