Ball-and-chain inactivation in a calcium-gated potassium channel

doi:10.1038/s41586-020-2116-0

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2116-0
	Ball-and-chain inactivation in a calcium-gated potassium channel
	Peron, Simon 1,2; Pancholi, Ravi 2; Voelcker, Bettina 2; Wittenbach, Jason D.1; olafsdottir, H. Freyja 1,3,4; Freeman, Jeremy 1; Svoboda, Karel 1
	2020-03-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	580 期号:7802 页码:288-+
文章类型	Article
语种	英语
国家	USA; Australia; Netherlands
英文关键词	Cryo-electron microscopy structures and molecular dynamics simulations of the calcium-activated potassium channel MthK from Methanobacterium thermoautotrophicum are used to show that gating of this channel involves a ball-and-chain inactivation mechanism mediated by a previously unresolved N-terminal peptide. Inactivation is the process by which ion channels terminate ion flux through their pores while the opening stimulus is still present(1). In neurons, inactivation of both sodium and potassium channels is crucial for the generation of action potentials and regulation of firing frequency(1,2). A cytoplasmic domain of either the channel or an accessory subunit is thought to plug the open pore to inactivate the channel via a ' ball-and-chain' mechanism(3-7). Here we use cryo-electron microscopy to identify the molecular gating mechanism in calcium-activated potassium channels by obtaining structures of the MthK channel from Methanobacterium thermoautotrophicum-a purely calcium-gated and inactivating channel-in a lipid environment. In the absence of Ca2+, we obtained a single structure in a closed state, which was shown by atomistic simulations to be highly flexible in lipid bilayers at ambient temperature, with large rocking motions of the gating ring and bending of pore-lining helices. In Ca2+-bound conditions, we obtained several structures, including multiple open-inactivated conformations, further indication of a highly dynamic protein. These different channel conformations are distinguished by rocking of the gating rings with respect to the transmembrane region, indicating symmetry breakage across the channel. Furthermore, in all conformations displaying open channel pores, the N terminus of one subunit of the channel tetramer sticks into the pore and plugs it, with free energy simulations showing that this is a strong interaction. Deletion of this N terminus leads to functionally non-inactivating channels and structures of open states without a pore plug, indicating that this previously unresolved N-terminal peptide is responsible for a ball-and-chain inactivation mechanism.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000520406700006
WOS关键词	BEAM-INDUCED MOTION ; SHAKER K-CHANNELS ; CRYO-EM STRUCTURE ; MOLECULAR-DYNAMICS ; NMR STRUCTURE ; BK CHANNELS ; GATING RING ; VOLTAGE ; MTHK ; BLOCK
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281080
专题	地球科学资源环境科学气候变化
作者单位	1.Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA; 2.NYU, Ctr Neural Sci, New York, NY 10003 USA; 3.UCL, Dept Cell & Dev Biol, London, England; 4.Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands
推荐引用方式 GB/T 7714	Peron, Simon,Pancholi, Ravi,Voelcker, Bettina,et al. Ball-and-chain inactivation in a calcium-gated potassium channel[J]. NATURE,2020,580(7802):288-+.
APA	Peron, Simon.,Pancholi, Ravi.,Voelcker, Bettina.,Wittenbach, Jason D..,olafsdottir, H. Freyja.,...&Svoboda, Karel.(2020).Ball-and-chain inactivation in a calcium-gated potassium channel.NATURE,580(7802),288-+.
MLA	Peron, Simon,et al."Ball-and-chain inactivation in a calcium-gated potassium channel".NATURE 580.7802(2020):288-+.