人类嗅觉CNG通道组装、门控及钙调素调节的结构机制。

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-23 DOI:10.1038/s41467-025-64436-5

Jing Xue,Ninghai Gan,Weizhong Zeng,Youxing Jiang

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引用次数: 0

摘要

哺乳动物环核苷酸门控通道（CNG）在视觉和嗅觉信号传导中起着至关重要的作用。在嗅觉感觉神经元中，天然CNG通道作为由CNGA2、CNGA4和CNGB1b亚基组成的异源四聚体发挥作用，并由cAMP激活。钙调素（CaM）调节嗅觉CNG通道的活性，使其能够快速适应气味。在这里，我们展示了天然人类嗅觉CNGA2/A4/B1b通道在cam结合的封闭状态和cAMP结合的开放状态下的低温电镜结构，阐明了通道组装中2:1:1亚基化学计量的分子基础以及cAMP激活时不对称通道门控。结合结构和功能分析和AlphaFold预测，我们在CNGB1b的N端和c端分别定义了两个不同的CaM结合位点（CaM1和CaM2），揭示了Ca2+/CaM介导的天然嗅觉CNG通道快速抑制的分子机制。

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Structural mechanisms of assembly, gating, and calmodulin modulation of human olfactory CNG channel.

Mammalian cyclic nucleotide-gated (CNG) channels play crucial roles in visual and olfactory signal transduction. In olfactory sensory neurons, the native CNG channel functions as a heterotetramer consisting of CNGA2, CNGA4, and CNGB1b subunits and is activated by cAMP. Calmodulin (CaM) modulates the activity of the olfactory CNG channel, enabling rapid adaptation to odorants. Here we present cryo-EM structures of the native human olfactory CNGA2/A4/B1b channel in both CaM-bound closed and cAMP-bound open states, elucidating the molecular basis of the 2:1:1 subunit stoichiometry in channel assembly and the asymmetrical channel gating upon cAMP activation. Combining structural and functional analyses with AlphaFold prediction, we define two distinct CaM binding sites (CaM1 and CaM2) on the N- and C-terminal regions of CNGB1b, respectively, shedding light on the molecular mechanism of Ca2+/CaM-mediated rapid inhibition of the native olfactory CNG channel.

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.