Cell Reports ( IF 7.5 ) Pub Date : 2021-08-24 , DOI: 10.1016/j.celrep.2021.109619 Yamuna Kalyani Mathiharan 1 , Ian W Glaaser 2 , Yulin Zhao 2 , Michael J Robertson 1 , Georgios Skiniotis 1 , Paul A Slesinger 2
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G-protein-gated inwardly rectifying potassium (GIRK) channels are important for determining neuronal excitability. In addition to G proteins, GIRK channels are potentiated by membrane cholesterol, which is elevated in the brains of people with neurodegenerative diseases such as Alzheimer’s dementia and Parkinson’s disease. The structural mechanism of cholesterol modulation of GIRK channels is not well understood. In this study, we present cryo- electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) and phosphatidylinositol 4,5-bisphosphate (PIP2). The structures reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain. Our structural analysis suggests that CHS stabilizes PIP2 interaction with the channel and promotes engagement of the cytoplasmic domain onto the transmembrane region. Mutagenesis of one of the CHS binding pockets eliminates cholesterol-dependent potentiation of GIRK2. Elucidating the structural mechanisms underlying cholesterol modulation of GIRK2 channels could facilitate the development of therapeutics for treating neurological diseases.
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中文翻译：
胆固醇和 PIP2 对 GIRK2 通道调节的结构洞察
G 蛋白门控内向整流钾 (GIRK) 通道对于确定神经元兴奋性很重要。除了 G 蛋白外，GIRK 通道还受到膜胆固醇的增强，膜胆固醇在阿尔茨海默氏症和帕金森氏症等神经退行性疾病患者的大脑中升高。GIRK 通道的胆固醇调节的结构机制尚不清楚。在这项研究中，我们展示了 GIRK2 在存在和不存在胆固醇类似物胆固醇半琥珀酸酯 (CHS) 和磷脂酰肌醇 4,5-二磷酸 (PIP 2 ) 的情况下的低温电子显微镜 (cryoEM) 结构。这些结构表明 CHS 在 PIP 2附近结合在跨膜结构域的面向脂质的疏水口袋中。我们的结构分析表明，CHS 稳定了 PIP 2与通道的相互作用，并促进了细胞质结构域与跨膜区域的结合。CHS结合口袋之一的诱变消除了GIRK2的胆固醇依赖性增强。阐明 GIRK2 通道的胆固醇调节的结构机制可以促进治疗神经系统疾病的疗法的发展。
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