Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel

Abstract

The calcium-permeable transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types 1-3. Channel activation requires binding of both ADP-ribose (ADPR) 2,4-6 and Ca2+ 7. The recently published TRPM2 structures from Danio rerio in the ligand-free and in the ADPR/Ca2+-bound conditions represent the channel in closed and open states, which uncover substantial tertiary and quaternary conformational rearrangements 8. However, it is unclear how these rearrangements occur within the tetrameric channel during channel gating. Here we report two cryo-electron microscopy structures of TRPM2 from the same species in complex with Ca2+ alone, and with both ADPR and Ca2+, determined to an overall resolution of ~3.8 [A] and ~4.2 [A] respectively. In comparison with the published results, our studies capture TRPM2 in two-fold symmetric intermediate states, offering a glimpse of the structural transitions within the tetramer that bridge the closed and open conformations.