W.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, 11724, USA.
Nat Commun. 2023 Jun 28;14(1):3821. doi: 10.1038/s41467-023-39388-3.
Calcium homeostasis modulator 1 (CALHM1) is a voltage-dependent channel involved in neuromodulation and gustatory signaling. Despite recent progress in the structural biology of CALHM1, insights into functional regulation, pore architecture, and channel blockade remain limited. Here we present the cryo-EM structure of human CALHM1, revealing an octameric assembly pattern similar to the non-mammalian CALHM1s and the lipid-binding pocket conserved across species. We demonstrate by MD simulations that this pocket preferentially binds a phospholipid over cholesterol to stabilize its structure and regulate the channel activities. Finally, we show that residues in the amino-terminal helix form the channel pore that ruthenium red binds and blocks.
钙稳态调节剂 1（CALHM1）是一种电压依赖性通道，参与神经调节和味觉信号传递。尽管在 CALHM1 的结构生物学方面取得了最近的进展，但对其功能调节、孔道结构和通道阻断的了解仍然有限。本文呈现了人源 CALHM1 的冷冻电镜结构，揭示了一种类似于非哺乳动物 CALHM1 的八聚体组装模式，以及在物种间保守的脂质结合口袋。通过 MD 模拟，我们证明了这个口袋优先与磷脂而不是胆固醇结合，以稳定其结构并调节通道活性。最后，我们表明，氨基末端螺旋中的残基形成了钌红结合和阻断的通道孔。
