Electron cryo-microscopy structure of the canonical TRPC4 ion channel.

Deivanayagabarathy Vinayagam,Christos Gatsogiannis,Amir Apelbaum,Arne Bothe,Felipe Merino,Thomas Mager,Stefan Raunser,Oliver Hofnagel

doi:10.7554/elife.36615

Deivanayagabarathy Vinayagam, Christos Gatsogiannis + Show 6 more

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https://doi.org/10.7554/elife.36615

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Abstract

Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+ signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of zebrafish TRPC4 in its unliganded (apo), closed state at an overall resolution of 3.6 Å. The structure reveals the molecular architecture of the cation conducting pore, including the selectivity filter and lower gate. The cytoplasmic domain contains two key hubs that have been shown to interact with modulating proteins. Structural comparisons with other TRP channels give novel insights into the general architecture and domain organization of this superfamily of channels and help to understand their function and pharmacology.

Highlights

Transient receptor potential (TRP) channels constitute a large superfamily of ion channels that can be grouped in seven subfamilies: transient receptor channels (TRPC), TRPM, TRPML, TRPP, TRPV, TRPA and TRPN (Montell, 2005)
We planned to heterologously express human TRPC4 in HEK293 cells and purify it to determine its structure by single particle cryo-EM
The measurements demonstrated that, like human TRPC4 (Akbulut et al, 2015), TRPC4DR can be activated by (-)-Englerin A resulting in similar currents (Figure 1)

Summary

Introduction

Transient receptor potential (TRP) channels constitute a large superfamily of ion channels that can be grouped in seven subfamilies: TRPC, TRPM, TRPML, TRPP, TRPV, TRPA and TRPN (Montell, 2005). Of the final data set (Figure 2—figure supplement 3) revealed that the lower cytoplasmic part of TRPC4DR is flexible, whereas the transmembrane domain is not (Video 2).

Results

Conclusion