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

Summary: 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...

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Autores principales:	Xiafei Yu, Yuan Xie, Xiaokang Zhang, Cheng Ma, Likun Liu, Wenxuan Zhen, Lingyi Xu, Jianmin Zhang, Yan Liang, Lixia Zhao, Xiuxia Gao, Peilin Yu, Jianhong Luo, Lin-Hua Jiang, Yan Nie, Fan Yang, Jiangtao Guo, Wei Yang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	structure of TRPM2 channel selectivity filter Ag+ modification computational modeling Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/033b93d8d1d24aa1ad3a824d21df3eb9
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spelling	oai:doaj.org-article:033b93d8d1d24aa1ad3a824d21df3eb92021-11-18T04:48:01ZStructural and functional basis of the selectivity filter as a gate in human TRPM2 channel2211-124710.1016/j.celrep.2021.110025https://doaj.org/article/033b93d8d1d24aa1ad3a824d21df3eb92021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721015072https://doaj.org/toc/2211-1247Summary: 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.Xiafei YuYuan XieXiaokang ZhangCheng MaLikun LiuWenxuan ZhenLingyi XuJianmin ZhangYan LiangLixia ZhaoXiuxia GaoPeilin YuJianhong LuoLin-Hua JiangYan NieFan YangJiangtao GuoWei YangElsevierarticlestructure of TRPM2 channelselectivity filterAg+ modificationcomputational modelingBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 7, Pp 110025- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	structure of TRPM2 channel selectivity filter Ag+ modification computational modeling Biology (General) QH301-705.5
spellingShingle	structure of TRPM2 channel selectivity filter Ag+ modification computational modeling Biology (General) QH301-705.5 Xiafei Yu Yuan Xie Xiaokang Zhang Cheng Ma Likun Liu Wenxuan Zhen Lingyi Xu Jianmin Zhang Yan Liang Lixia Zhao Xiuxia Gao Peilin Yu Jianhong Luo Lin-Hua Jiang Yan Nie Fan Yang Jiangtao Guo Wei Yang Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
description	Summary: 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.
format	article
author	Xiafei Yu Yuan Xie Xiaokang Zhang Cheng Ma Likun Liu Wenxuan Zhen Lingyi Xu Jianmin Zhang Yan Liang Lixia Zhao Xiuxia Gao Peilin Yu Jianhong Luo Lin-Hua Jiang Yan Nie Fan Yang Jiangtao Guo Wei Yang
author_facet	Xiafei Yu Yuan Xie Xiaokang Zhang Cheng Ma Likun Liu Wenxuan Zhen Lingyi Xu Jianmin Zhang Yan Liang Lixia Zhao Xiuxia Gao Peilin Yu Jianhong Luo Lin-Hua Jiang Yan Nie Fan Yang Jiangtao Guo Wei Yang
author_sort	Xiafei Yu
title	Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
title_short	Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
title_full	Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
title_fullStr	Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
title_full_unstemmed	Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel
title_sort	structural and functional basis of the selectivity filter as a gate in human trpm2 channel
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/033b93d8d1d24aa1ad3a824d21df3eb9
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Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel

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