1. Academic Validation
  2. Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel

Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel

  • Cell Rep. 2021 Nov 16;37(7):110025. doi: 10.1016/j.celrep.2021.110025.
Xiafei Yu 1 Yuan Xie 2 Xiaokang Zhang 3 Cheng Ma 4 Likun Liu 1 Wenxuan Zhen 5 Lingyi Xu 2 Jianmin Zhang 1 Yan Liang 6 Lixia Zhao 7 Xiuxia Gao 7 Peilin Yu 6 Jianhong Luo 8 Lin-Hua Jiang 9 Yan Nie 8 Fan Yang 10 Jiangtao Guo 11 Wei Yang 12
Affiliations

Affiliations

  • 1 Departments of Biophysics and Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
  • 2 Departments of Biophysics and Pathology of Sir Run 14, Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China.
  • 3 Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China; Interdisciplinary Center for Brain Information, The Brain Cognition and Brain Disease Institute, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, Guangdong 518055, China.
  • 4 Co-facility center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
  • 5 Department of Biophysics and Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
  • 6 Departments of Toxicology and Medical Oncology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, P. R. China.
  • 8 Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China.
  • 9 School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK; Sino-UK Joint Laboratory of Brain Function and Injury, Department of Physiology and Neurobiology, Xinxiang Medical University, Xinxiang, P. R. China.
  • 10 Department of Biophysics and Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China. Electronic address: [email protected].
  • 11 Departments of Biophysics and Pathology of Sir Run 14, Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P. R. China. Electronic address: [email protected].
  • 12 Departments of Biophysics and Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P. R. China. Electronic address: [email protected].
Abstract

Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel, is gated by intracellular adenosine diphosphate ribose (ADPR), Ca2+, warm temperature, and oxidative stress. It is critically involved in physiological and pathological processes ranging from inflammation to stroke to neurodegeneration. At present, the channel's gating and ion permeation mechanisms, such as the location and identity of the selectivity filter, remain ambiguous. Here, we report the cryo-electron microscopy (cryo-EM) structure of human TRPM2 in nanodisc in the ligand-free state. Cryo-EM map-guided computational modeling and patch-clamp recording further identify a quadruple-residue motif as the ion selectivity filter, which adopts a restrictive conformation in the closed state and acts as a gate, profoundly contrasting with its widely open conformation in the Nematostella vectensis TRPM2. Our study reveals the gating of human TRPM2 by the filter and demonstrates the feasibility of using cryo-EM in conjunction with computational modeling and functional studies to garner structural information for intrinsically dynamic but functionally important domains.

Keywords

Ag(+) modification; computational modeling; selectivity filter; structure of TRPM2 channel.

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