Cryo-EM structure of human heptameric pannexin 2 channel PMID: 36869038

RQC and Longevity Regulation

2026-09-03

Cryo-EM structure of human heptameric pannexin 2 channel

Nat Commun. 2023 Mar 3;14(1):1118. doi: 10.1038/s41467-023-36861-x.

Hang Zhang ¹ , Shiyu Wang ² , Zhenzhen Zhang ¹ , Mengzhuo Hou ¹ , Chunyu Du ³ , Zhenye Zhao ² , Horst Vogel ² , Zhifang Li ¹ , Kaige Yan ⁴ , Xiaokang Zhang ⁵ ⁶ ⁷ , Jianping Lu ³ , Yujie Liang ³ , Shuguang Yuan ⁸ , Daping Wang ⁹ ¹⁰ , Huawei Zhang ¹¹ ¹²

Affiliations

1. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.
2. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
3. Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, 518020, China.
4. School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
5. Interdisciplinary Center for Brain Information, The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
6. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
7. Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong, 518055, China.
8. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. [email protected].
9. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
10. Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518000, China. [email protected].
11. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
12. Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].

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.