期刊
STRUCTURE
卷 23, 期 8, 页码 1404-1413出版社
CELL PRESS
DOI: 10.1016/j.str.2015.05.018
关键词
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资金
- Spanish Ministry of Science and Innovation [SAF2010-16725, SAF2012-38140]
- Fondo de Investigacion Sanitaria [Red HERACLES RD12/0042/0014]
- FEDER Funds
- Millennium Scientific Initiative of the Ministerio de Economia, Fomento y Turismo [P029-022-F]
- FONDECYT grant [1131003]
- CONICYT-PIA [ACT-1107]
- CONICYT-PCHA/Doctorado Nacional [2013-21130631]
Functional transient receptor potential (TRP) channels result from the assembly of four subunits. Here, we show an interaction between the pre-S1, TRP, and the ankyrin repeat domain (ARD)-S1 linker domains of TRPV1 and TRPV4 that is essential for proper channel assembly. Neutralization of TRPV4 pre-S1 K462 resulted in protein retention in the ER, defective glycosylation and trafficking, and unresponsiveness to TRPV4-activating stimuli. Similar results were obtained with the equivalent mutation in TRPV1 pre-S1. Molecular dynamics simulations revealed that TRPV4-K462 generated an alternating hydrogen network with E745 (TRP box) and D425 (pre-S1 linker), and that K462Q mutation affected subunit folding. Consistently, single TRPV4-E745A or TRPV4-D425A mutations moderately affected TRPV4 biogenesis while double TRPV4-D425A/E745A mutation resumed the TRPV4-K462Q phenotype. Thus, the interaction between pre-S1, TRP, and linker domains is mandatory to generate a structural conformation that allows the contacts between adjacent subunits to promote correct assembly and trafficking to the plasma membrane.
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