Atomistic mechanisms of the regulation of small- conductance Ca2+- activated K plus channel (SK2) by PIP2

• 成果类型: Article
• 署名作者: Woltz, Ryan L.; Zheng, Yang; Choi, Woori; Ngo, Khoa; Trinh, Pauline; Ren, Lu; Thai, Phung N.; Harris, Brandon J.; Han, Yanxiao; Rouen, Kyle C.; Mateos, Diego Lopez; Jian, Zhong; Chen-Izu, Ye; Dickson, Eamonn J.; Yamoah, Ebenezer N.; Yarov-Yarovoy, Vladimir; Vorobyov, Igor; Zhang, Xiao-Dong; Chiamvimonvat, Nipavan
• 署名单位: University of California System; University of California Davis; University of California System; University of California Davis; Stanford University; University of California System; University of California Davis; University of Arizona; University of California System; University of California Davis; University of Arizona
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10880
• DOI: 10.1073/pnas.2318900121
• 发表日期: 2024-09-24
• 关键词: surface-membrane expression; potassium channels; atrial-fibrillation; functional roles; voltage sensor; protein; alpha-actinin2; subunits; domains; form

摘要

Small- conductance Ca2+-activated K+ channels (SK, KCa2) are gated solely by intracellular microdomain Ca2+. 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 Ca2+ 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 Ca2+-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.