Cryo-EM structure of human heptameric pannexin 2 channel

Hang Zhang, Shiyu Wang, Zhenzhen Zhang, Mengzhuo Hou, Chunyu Du, Zhenye Zhao, Horst Vogel, Zhifang Li, Kaige Yan, Xiaokang Zhang, Jianping Lu, Yujie Liang, Shuguang Yuan (), Daping Wang () and Huawei Zhang ()
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Hang Zhang: Southern University of Science and Technology
Shiyu Wang: Chinese Academy of Sciences
Zhenzhen Zhang: Southern University of Science and Technology
Mengzhuo Hou: Southern University of Science and Technology
Chunyu Du: Shenzhen Kangning Hospital, Shenzhen Mental Health Center
Zhenye Zhao: Chinese Academy of Sciences
Horst Vogel: Chinese Academy of Sciences
Zhifang Li: Southern University of Science and Technology
Kaige Yan: Southern University of Science and Technology
Xiaokang Zhang: Chinese Academy of Sciences
Jianping Lu: Shenzhen Kangning Hospital, Shenzhen Mental Health Center
Yujie Liang: Shenzhen Kangning Hospital, Shenzhen Mental Health Center
Shuguang Yuan: Chinese Academy of Sciences
Daping Wang: Southern University of Science and Technology
Huawei Zhang: Southern University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Pannexin 2 (Panx2) is a large-pore ATP-permeable channel with critical roles in various physiological processes, such as the inflammatory response, energy production and apoptosis. Its dysfunction is related to numerous pathological conditions including ischemic brain injury, glioma and glioblastoma multiforme. However, the working mechanism of Panx2 remains unclear. Here, we present the cryo-electron microscopy structure of human Panx2 at a resolution of 3.4 Å. Panx2 structure assembles as a heptamer, forming an exceptionally wide channel pore across the transmembrane and intracellular domains, which is compatible with ATP permeation. Comparing Panx2 with Panx1 structures in different states reveals that the Panx2 structure corresponds to an open channel state. A ring of seven arginine residues located at the extracellular entrance forms the narrowest site of the channel, which serves as the critical molecular filter controlling the permeation of substrate molecules. This is further verified by molecular dynamics simulations and ATP release assays. Our studies reveal the architecture of the Panx2 channel and provide insights into the molecular mechanism of its channel gating.

Date: 2023
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DOI: 10.1038/s41467-023-36861-x

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