Solution structure of extracellular loop of human beta 4 subunit of BK channel and its biological implication on ChTX sensitivity

doi:10.1038/s41598-018-23016-y

	Solution structure of extracellular loop of human beta 4 subunit of BK channel and its biological implication on ChTX sensitivity
	Wang, Yanting 1,2; Lan, Wenxian 1; Yan, Zhenzhen 2; Gao, Jing 3; Liu, Xinlian 1; Wang, Sheng 2; Guo, Xiying 2; Wang, Chunxi 1; Zhou, Hu3 ; Ding, Jiuping 2
刊名	SCIENTIFIC REPORTS
	2018-03-15
卷号	8
ISSN号	2045-2322
DOI	10.1038/s41598-018-23016-y
文献子类	Article
英文摘要	Large-conductance Ca2+- and voltage-dependent K+ (BK) channels display diverse biological functions while their pore-forming a subunit is coded by a single Slo1 gene. The variety of BK channels is correlated with the effects of BK alpha coexpression with auxiliary beta (beta 1-beta 4) subunits, as well as newly defined. subunits. Charybdotoxin (ChTX) blocks BK channel through physically occluding the K+-conduction pore. Human brain enriched beta 4 subunit (h beta 4) alters the conductance-voltage curve, slows activation and deactivation time courses of BK channels. Its extracellular loop (h beta 4-loop) specifically impedes ChTX to bind BK channel pore. However, the structure of beta 4 subunit's extracellular loop and the molecular mechanism for gating kinetics, toxin sensitivity of BK channels regulated by beta 4 are still unclear. To address them, here, we first identified four disulfide bonds in h beta 4-loop by mass spectroscopy and NMR techniques. Then we determined its three-dimensional solution structure, performed NMR titration and electrophysiological analysis, and found that residue Asn123 of beta 4 subunit regulated the gating and pharmacological characteristics of BK channel. Finally, by constructing structure models of BK alpha/beta 4 and thermodynamic double-mutant cycle analysis, we proposed that BKa subunit might interact with beta 4 subunit through the conserved residue Glu264(BK alpha) coupling with residue Asn123(beta 4).
资助项目	National Key R&D Program of China[2016YFA0502302] ; National Key R&D Program of China[2017YPE0108200] ; Chinese Academy of Sciences[XDB 20000000] ; National Science Foundation of China (NSFC)[91753119] ; National Science Foundation of China (NSFC)[21472229] ; National Science Foundation of China (NSFC)[21778065] ; Fundamental Research Funds for the Central Universities[2016YXMS261]
WOS关键词	CA2+-ACTIVATED K+ CHANNEL ; ACTIVATED POTASSIUM CHANNEL ; DOUBLE-MUTANT CYCLES ; LARGE-CONDUCTANCE ; TRANSMEMBRANE HELICES ; PROTEIN-STRUCTURE ; NERVOUS-SYSTEM ; AUXILIARY BETA ; MODULATION ; VOLTAGE
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000427459200003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279850]
专题	分析化学研究室
通讯作者	Cao, Chunyang
作者单位	1.Chinese Acad Sci, State Key Lab Bioorgan & Nat Prod Chem, Ctr Excellence Mol Synth, Shanghai Inst Organ Chem, 345 Lingling Rd, Shanghai 200032, Peoples R China; 2.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Key Lab Mol Biophys, Minist Educ, 1037 Luoyu Rd, Wuhan 430074, Hubei, Peoples R China; 3.Chinese Acad Sci, Dept Analyt Chem, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China; 5.Chinese Acad Sci, Collaborat Innovat Ctr Chem Life Sci, 345 Lingling Rd, Shanghai 200032, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yanting,Lan, Wenxian,Yan, Zhenzhen,et al. Solution structure of extracellular loop of human beta 4 subunit of BK channel and its biological implication on ChTX sensitivity[J]. SCIENTIFIC REPORTS,2018,8.
APA	Wang, Yanting.,Lan, Wenxian.,Yan, Zhenzhen.,Gao, Jing.,Liu, Xinlian.,...&Cao, Chunyang.(2018).Solution structure of extracellular loop of human beta 4 subunit of BK channel and its biological implication on ChTX sensitivity.SCIENTIFIC REPORTS,8.
MLA	Wang, Yanting,et al."Solution structure of extracellular loop of human beta 4 subunit of BK channel and its biological implication on ChTX sensitivity".SCIENTIFIC REPORTS 8(2018).