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Structure and assembly of calcium homeostasis modulator proteins.
Nature Structural & Molecular Biology ( IF 16.8 ) Pub Date : 2020-01-27 , DOI: 10.1038/s41594-019-0369-9
Johanna L Syrjanen 1 , Kevin Michalski 1 , Tsung-Han Chou 1 , Timothy Grant 2 , Shanlin Rao 3, 4 , Noriko Simorowski 1 , Stephen J Tucker 3 , Nikolaus Grigorieff 2, 5 , Hiro Furukawa 1
Affiliation  

The biological membranes of many cell types contain large-pore channels through which a wide variety of ions and metabolites permeate. Examples include connexin, innexin and pannexin, which form gap junctions and/or bona fide cell surface channels. The most recently identified large-pore channels are the calcium homeostasis modulators (CALHMs), through which ions and ATP permeate in a voltage-dependent manner to control neuronal excitability, taste signaling and pathologies of depression and Alzheimer's disease. Despite such critical biological roles, the structures and patterns of their oligomeric assembly remain unclear. Here, we reveal the structures of two CALHMs, chicken CALHM1 and human CALHM2, by single-particle cryo-electron microscopy (cryo-EM), which show novel assembly of the four transmembrane helices into channels of octamers and undecamers, respectively. Furthermore, molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger CALHM2 pore, but not within CALHM1, demonstrating the potential correlation between pore size, lipid accommodation and channel activity.

中文翻译:

钙稳态调节蛋白的结构和组装。

许多细胞类型的生物膜都包含大孔通道,各种离子和代谢物可以通过这些通道渗透。例子包括连接蛋白、innexin 和 pannexin,它们形成间隙连接和/或真正的细胞表面通道。最近发现的大孔通道是钙稳态调节剂 (CALHM),离子和 ATP 通过它以电压依赖性方式渗透,以控制神经元兴奋性、味觉信号传导以及抑郁症和阿尔茨海默病的病理。尽管具有如此重要的生物学作用,但其寡聚组装的结构和模式仍不清楚。在这里,我们通过单粒子低温电子显微镜 (cryo-EM) 揭示了两种 CALHM,鸡 CALHM1 和人 CALHM2 的结构,这显示了四个跨膜螺旋分别组装成八聚体和十一聚体的通道。此外,分子动力学模拟表明,脂质可以在较大的 CALHM2 孔内有利地组装成双层,但在 CALHM1 内则不然,这证明了孔径、脂质调节和通道活性之间的潜在相关性。
更新日期:2020-01-27
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