Garcia-Elias, AnnaBerna-Erro, AlejandroRubio-Moscardo, FannyPardo-Pastor, CarlosMrkonjić, SanelaSepúlveda, Romina V.Vicente, RubénGonzález-Nilo, FernandoValverde, Miguel A.2023-03-242023-03-242015-08Structure Volume 23, Issue 8, Pages 1404 - 14137 August 2015 Article number 32020969-2126https://repositorio.unab.cl/xmlui/handle/ria/47852Indexación: ScopusSummary 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. © 2015 Elsevier Ltd.enTransient Receptor Potential ChannelsAnimalsRN 1734ArtículoAtribución 4.0 Internacional (CC BY 4.0)10.1016/j.str.2015.05.018