A TRPV4 Channel C-terminal Folding Recognition Domain Critical for   Trafficking and Function

doi:10.1074/jbc.M113.457291

CORC > 北京大学 > 心理与认知科学学院

	A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function
	Lei, Lei ; Cao, Xu ; Yang, Fan ; Shi, Di-Jing ; Tang, Yi-Quan ; Zheng, Jie ; Wang, Kewei
刊名	journal of biological chemistry
	2013
关键词	RECEPTOR POTENTIAL VANILLOID-4 NONSELECTIVE CATION CHANNEL CALMODULIN-BINDING SITE ION-CHANNEL ENDOPLASMIC-RETICULUM PORE TURRET VR-OAC ACTIVATION SENSITIVITY PATHWAYS
DOI	10.1074/jbc.M113.457291
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.; http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000317565000023&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701 ; Biochemistry & Molecular Biology; SCI(E); EI; PubMed; 13; ARTICLE; 15; 10427-10439; 288
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/342938]
专题	心理与认知科学学院
推荐引用方式 GB/T 7714	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.
APA	Lei, Lei.,Cao, Xu.,Yang, Fan.,Shi, Di-Jing.,Tang, Yi-Quan.,...&Wang, Kewei.(2013).A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function.journal of biological chemistry.
MLA	Lei, Lei,et al."A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function".journal of biological chemistry (2013).