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学科主题: 基础医学
题名:
A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function
作者: Lei, Lei1; Cao, Xu1; Yang, Fan2; Shi, Di-Jing1; Tang, Yi-Quan1; Zheng, Jie2; Wang, Kewei1,3,4
刊名: JOURNAL OF BIOLOGICAL CHEMISTRY
发表日期: 2013-04-12
DOI: 10.1074/jbc.M113.457291
卷: 288, 期:15, 页:10427-10439
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology
研究领域[WOS]: Biochemistry & Molecular Biology
关键词[WOS]: RECEPTOR POTENTIAL VANILLOID-4 ; NONSELECTIVE CATION CHANNEL ; CALMODULIN-BINDING SITE ; ION-CHANNEL ; ENDOPLASMIC-RETICULUM ; PORE TURRET ; VR-OAC ; ACTIVATION ; SENSITIVITY ; PATHWAYS
英文摘要:

The Ca2+-permeable transient receptor potential vanilloid subtype 4 (TRPV4) channel mediates crucial physiological functions, such as calcium signaling, temperature sensing, and maintaining cell volume and energy homeostasis. Noticeably, most disease-causing genetic mutations are concentrated in the cytoplasmic domains. In the present study, we focused on the role of the TRPV4 C terminus in modulating protein folding, trafficking, and activity. By examining a series of C-terminal deletions, we identified a 20-amino acid distal region covering residues 838-857 that is critical for channel folding, maturation, and trafficking. Surface biotinylation, confocal imaging, and fluorescence-based calcium influx assay demonstrated that mutant proteins missing this region were trapped in the endoplasmic reticulum and unglycosylated, leading to accelerated degradation and loss of channel activity. Rosetta de novo structural modeling indicated that residues 838-857 assume a defined conformation, with Gly(849) and Pro(851) located at critical positions. Patch clamp recordings confirmed that lowering the temperature from 37 to 30 degrees C rescued channel activity of folding-defective mutants. Moreover, biochemical tests demonstrated that, in addition to participating in C-C interaction, the C terminus also interacts with the N terminus. Taken together, our findings indicate that the C-terminal region of TRPV4 is critical for channel protein folding and maturation, and the short distal segment plays an essential role in this process. Therefore, selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain and skeletal dysplasias.

语种: 英语
所属项目编号: R01NS072377 ; 30970919 ; 81221002 ; B07001 ; 2013CB531300
项目资助者: National Institutes of Health ; National Science Foundation of China ; Ministry of Education of China ; Ministry of Science and Technology of China
WOS记录号: WOS:000317565000023
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62661
Appears in Collections:基础医学院_神经生物学系_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Dept Neurobiol, Neurosci Res Inst, Beijing 100191, Peoples R China
2.Univ Calif Davis, Sch Med, Dept Physiol & Membrane Biol, Davis, CA 95616 USA
3.Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
4.Peking Univ, PKU IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China

Recommended Citation:
Lei, Lei,Cao, Xu,Yang, Fan,et al. A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2013,288(15):10427-10439.
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