globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1718373115
论文题名:
Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating
作者: Yeung P.S.-W.; Yamashita M.; Ing C.E.; Pomès R.; Freymann D.M.; Prakriya M.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2018
卷: 115, 期:22
起始页码: E5193
结束页码: E5202
语种: 英语
英文关键词: Calcium ; CRAC channels ; Orai1 ; STIM1 ; Store-operated calcium entry
Scopus关键词: calcium release activated calcium channel 1 ; cysteine ; stromal interaction molecule 1 ; calcium ; calcium release activated calcium channel 1 ; ORAI1 protein, human ; allosterism ; alpha helix ; Article ; channel gating ; conformational transition ; functional anatomy ; gene cluster ; gene locus ; hydrophobicity ; molecular dynamics ; mutagenesis ; mutational analysis ; priority journal ; protein domain ; protein function ; signal transduction ; chemistry ; genetics ; human ; metabolism ; protein domain ; Calcium ; Humans ; Molecular Dynamics Simulation ; ORAI1 Protein ; Protein Domains
英文摘要: Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1–4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing these contacts via mutagenesis destabilizes STIM1-mediated Orai1 channel gating, indicating that these bridges between TM1 and the surrounding TM2/3 ring are critical for conveying the gating signal to the pore. These findings help develop a framework for understanding the global conformational changes and allosteric interactions between topologically distinct domains that are essential for activation of Orai1 channels. © 2018 National Academy of Sciences. All rights reserved.
Citation statistics:
资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163704
Appears in Collections:气候变化与战略

Files in This Item:

There are no files associated with this item.


作者单位: Yeung, P.S.-W., Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Yamashita, M., Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Ing, C.E., Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada, Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Pomès, R., Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada, Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Freymann, D.M., Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Prakriya, M., Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States

Recommended Citation:
Yeung P.S.-W.,Yamashita M.,Ing C.E.,et al. Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating[J]. Proceedings of the National Academy of Sciences of the United States of America,2018-01-01,115(22)
Service
Recommend this item
Sava as my favorate item
Show this item's statistics
Export Endnote File
Google Scholar
Similar articles in Google Scholar
[Yeung P.S.-W.]'s Articles
[Yamashita M.]'s Articles
[Ing C.E.]'s Articles
百度学术
Similar articles in Baidu Scholar
[Yeung P.S.-W.]'s Articles
[Yamashita M.]'s Articles
[Ing C.E.]'s Articles
CSDL cross search
Similar articles in CSDL Cross Search
[Yeung P.S.-W.]‘s Articles
[Yamashita M.]‘s Articles
[Ing C.E.]‘s Articles
Related Copyright Policies
Null
收藏/分享
所有评论 (0)
暂无评论
 

Items in IR are protected by copyright, with all rights reserved, unless otherwise indicated.