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Abstract
NompC is a mechanosensitive ion channel responsible for the sensation of touch and balance in Drosophila melanogaster. Based on a resolved cryo-EM structure, we performed all-atom molecular dynamics simulations and electrophysiological experiments to study the atomistic details of NompC gating. Our results showed that NompC could be opened by compression of the intracellular ankyrin repeat domain but not by a stretch, and a number of hydrogen bonds along the force convey pathway are important for the mechanosensitivity. Under intracellular compression, the bundled ankyrin repeat region acts like a spring with a spring constant of ~13 pN nm-1 by transferring forces at a rate of ~1.8 nm ps-1. The linker helix region acts as a bridge between the ankyrin repeats and the transient receptor potential (TRP) domain, which passes on the pushing force to the TRP domain to undergo a clockwise rotation, resulting in the opening of the channel. This could be the universal gating mechanism of similar tethered mechanosensitive TRP channels, which enable cells to feel compression and shrinkage.
Highlights
Many types of sensations initiate from the gating of transient receptor potential (TRP) ion channels, which regulate the intracellular cation concentration that triggers downstream signaling pathways (Montell et al, 2002; Mutai and Heller, 2003; Pedersen et al, 2005; Basbaum et al, 2009; Cheng et al, 2010a; Fowler and Montell, 2013)
For the TM + linker helix (LH) system, we applied forces that are normal to the membrane surface on the AR29, which directly connects to the LH region, and we monitored how the TM domain responds by calculating the radius of the TM pore
We observed that the channel remains closed throughout the simulations without any external forces (Figure 1B and Figure 1—figure supplement 2A, Video 1), indicating that the closed-state cryo-EM structure was stable in our ‘force-free’ molecular dynamics (MD) simulations
Summary
Many types of sensations initiate from the gating of transient receptor potential (TRP) ion channels, which regulate the intracellular cation concentration that triggers downstream signaling pathways (Montell et al, 2002; Mutai and Heller, 2003; Pedersen et al, 2005; Basbaum et al, 2009; Cheng et al, 2010a; Fowler and Montell, 2013). Sodium ions spontaneously permeated through the partially opened gate in the ‘pushing’ molecular dynamics (MD) simulations in the absence of a transmembrane potential in the trajectories CI1 and CI2, respectively. We provide a plausible push-to-open mechanism for the tethered ion channels, which may be used by cells to sense and respond to compression and shrinkage
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