Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1 , TRPV4

Title: Interaction between the Linker, Pre-S1, and TRP Domains Determines Folding, Assembly, and Trafficking of TRPV Channels.

Authors: Anna Garcia-Elias, Alejandro Berna-Erro, Fanny Rubio-Moscardó, Carlos Pardo-Pastor, Sanela Mrkonjic, Romina V Sepúlveda, Rubén Vicente, Fernando Gonzalez-Nilo, Miguel A Valverde

Journal, date & volume: Structure, 2015 Aug 4 , 23, 1404-13

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26146187

Abstract
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.