Molecular insights into the human CLC-7/Ostm1 transporter

doi:10.1126/sciadv.abb4747

	Molecular insights into the human CLC-7/Ostm1 transporter
	Zhang, Sensen 1; Liu, Yang 1; Zhang, Bing 2; Zhou, Jun 1; Li, Tianyu 3; Liu, Zhiqiang 2; Li, Yang 3; Yang, Maojun 1,4
刊名	SCIENCE ADVANCES
	2020-08-01
卷号	6 期号:33 页码:10
ISSN号	2375-2548
DOI	10.1126/sciadv.abb4747
通讯作者	Liu, Zhiqiang(drliuzhiqiang@163.com) ; Li, Yang() ; Yang, Maojun(maojunyang@tsinghua.edu.cn)
英文摘要	CLC family proteins translocate chloride ions across cell membranes to maintain the membrane potential, regulate the transepithelial Cl- transport, and control the intravesicular pH among different organelles. CLC-7/Ostm1 is an electrogenic Cl-/H+ antiporter that mainly resides in lysosomes and osteoclast ruffled membranes. Mutations in human CLC-7/Ostm1 lead to lysosomal storage disorders and severe osteopetrosis. Here, we present the cryoelectron microscopy (cryo-EM) structure of the human CLC-7/Ostm1 complex and reveal that the highly glycosylated Ostm1 functions like a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane. Our complex structure reveals a functionally crucial domain interface between the amino terminus, TMD, and CBS domains of CLC-7. Structural analyses and electrophysiology studies suggest that the domain interaction interfaces affect the slow gating kinetics of CLC-7/Ostm1. Thus, our study deepens understanding of CLC-7/Ostm1 transporter and provides insights into the molecular basis of the disease-related mutations.
资助项目	National Key R&D Program of China[2017YFA0504600] ; National Key R&D Program of China[2016YFA0501100] ; National Key R&D Program of China[2018ZX09711002] ; Fundamental Research Funds for the Central Universities[22120180534] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040220] ; National Science Fund for Distinguished Young Scholars[31625008] ; National Natural Science Foundation of China[21532004] ; National Natural Science Foundation of China[31570733] ; National Natural Science Foundation of China[81771188] ; National Natural Science Foundation of China[81901376] ; National Natural Science Foundation of China[31671049]
WOS关键词	AUTOSOMAL RECESSIVE OSTEOPETROSIS ; CLC CHLORIDE CHANNELS ; DOMINANT OSTEOPETROSIS ; REQUIRES OSTM1 ; MUTATIONS ; DISEASE ; IDENTIFICATION ; PORES ; CIC-7 ; LEADS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	AMER ASSOC ADVANCEMENT SCIENCE
WOS记录号	WOS:000560465800027
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292476]
专题	中国科学院上海药物研究所
通讯作者	Liu, Zhiqiang; Li, Yang; Yang, Maojun
作者单位	1.Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci,Minist Educ,Key Lab Prot Sci, Beijing 100084, Peoples R China 2.Tongji Univ, Shanghai Matern & Infant Hosp 1, Dept Anesthesiol, Sch Med, Shanghai 201204, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 4.Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Sensen,Liu, Yang,Zhang, Bing,et al. Molecular insights into the human CLC-7/Ostm1 transporter[J]. SCIENCE ADVANCES,2020,6(33):10.
APA	Zhang, Sensen.,Liu, Yang.,Zhang, Bing.,Zhou, Jun.,Li, Tianyu.,...&Yang, Maojun.(2020).Molecular insights into the human CLC-7/Ostm1 transporter.SCIENCE ADVANCES,6(33),10.
MLA	Zhang, Sensen,et al."Molecular insights into the human CLC-7/Ostm1 transporter".SCIENCE ADVANCES 6.33(2020):10.