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Atomistic mechanisms of the regulation of small-conductance Ca 2+ -activated K + channel (SK2) by PIP2
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-09-17 , DOI: 10.1073/pnas.2318900121
Ryan L Woltz 1 , Yang Zheng 1 , Woori Choi 1 , Khoa Ngo 2 , Pauline Trinh 1 , Lu Ren 3 , Phung N Thai 1 , Brandon J Harris 2 , Yanxiao Han 2 , Kyle C Rouen 2 , Diego Lopez Mateos 2 , Zhong Jian 4 , Ye Chen-Izu 4 , Eamonn J Dickson 2 , Ebenezer N Yamoah 5 , Vladimir Yarov-Yarovoy 2, 6 , Igor Vorobyov 2, 4 , Xiao-Dong Zhang 1 , Nipavan Chiamvimonvat 1, 4, 7, 8
Affiliation  

Small-conductance Ca 2+ -activated K + channels (SK, K Ca 2) are gated solely by intracellular microdomain Ca 2+ . The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca 2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca 2+ -CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

中文翻译:


PIP2 调节小电导 Ca 2+ 激活的 K + 通道 (SK2) 的原子机制



小电导 Ca 2+ 激活的 K + 通道 (SK, K Ca 2) 仅由细胞内微结构域 Ca 2+ 设门。该通道已成为心律失常的治疗靶点。钙调蛋白 (CaM) 与 SK 通道的 CaM 结合域 (CaMBD) 相互作用,作为通道门控的必需 Ca 2+ 传感器。在异源表达系统中,磷脂酰肌醇 4,5-二磷酸 (PIP2) 与 CaM 协调调节 SK 通道。然而,PIP2 在调节心肌细胞 SK 通道中的作用和机制仍然未知。在这里,光遗传学、磁性纳米粒子与 Rosetta 结构建模和分子动力学 (MD) 模拟相结合,揭示了 PIP2 如何在 SK 通道激活中与 Ca 2+ -CaM 协同工作的原子机制。我们的计算研究为氨基酸残基 R395 在 S6 跨膜片段中的关键作用提供了证据,该片段位于细胞内疏水门的亲缘关系中。该残基与相邻亚基的 S6 跨膜段中的残基 E398 形成盐桥。R395 和 E398 在所有已知的 SK 通道亚型中都是保守的。我们的研究结果表明,PIP2 与 R395 残基的结合破坏了 R395:E398 盐桥,增加了跨膜片段 S6 的灵活性和通道的激活。重要的是,我们的研究结果为测试 SK 通道家族的治疗性抑制剂和激活剂的基于结构的药物设计提供了一个平台。这项研究是及时的,因为 SK 通道抑制剂目前正在进行治疗房性心律失常的临床试验。
更新日期:2024-09-17
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