Push-to-open: The Gating Mechanism of the Tethered Mechanosensitive Ion Channel NompC

Abstract

NompC was one of the earliest identified mechanosensitive ion channels responsible for the sensation of touch and balance in Drosophila melanogaster. A tethered gating model was proposed for NompC and the Cryo-EM structure has been solved. However, the atomistic mechano-gating mechanism still remains elusive. Here we show the atomistic details of the NompC channel opening in response to the compression of the intracellular domain while remaining closed under an intracellular stretch. This is demonstrated by all-atom molecular dynamics simulations and evidenced by electrophysiological experiments. Under intracellular compression, the ankyrin repeat region undergoes a significant conformational change and passes the mechanical force to the linker helices like a spring with a force constant of ~3.3 pN/nm. The linker helix region acts as a bridge between the ankyrin repeats and TRP domain, and most of the mutations breaking the hydrogen bonds around this region lead to the loss-of-function of the channel. Eventually, the compression-induced mechanical force is passed from the linker helices onto the TRP domain, which then undergoes a clockwise rotation that leads to the opening of the channel. This work provides a clear picture of how a pushing force opens the mechanosensitive ion channel NompC,which might be a universal gating mechanism of similar tethered mechanosensitive ion channels, enabling cells to feel and respond to compression or shrinking.

Spatiotemporal Stop-and-go Dynamics of the Mitochondrial TOM Core Complex Correlates With Three-state Channel Activity

“…In our study, we provide in vitro evidence for the first example of a membrane β-barrel protein that exhibits membrane state-dependent mechanosensitive-like properties. Our findings are consistent with the "tether model" 33 , where an intermembrane protein anchor domain (here Tom22) limits lateral diffusion, as observed for a large number of α-helical membrane proteins 32,33,[38][39][40][41] . It will be interesting to study whether the in vitro properties of the TOM-CC can be confirmed in intact mitochondria.…”

Correlation of mitochondrial TOM core complex stop-and-go and open-closed channel dynamics

“…Mechanosensitivity via force transmission from a tether to the extracellular matrix and/or the cytoskeleton has been established for a number of -helical membrane proteins (Brohawn et al, 2014a(Brohawn et al, , 2014bGe et al, 2018;Jin et al, 2020;Kefauver et al, 2020;Martinac, 2004;Pliotas and Naismith, 2017;Teng et al, 2015;Yang Wang et al, 2019). These findings go along with our observations for the TOM-CC, which seems to obey the "tether model" proposed by Kefauver et al (2020) (Kefauver et al, 2020), where an intermembrane protein anchor domain limits lateral diffusion.…”

Discoveries in structure and physiology of mechanically activated ion channels

“…Atomic force microscopy measurements had previously shown that isolated NOMPC ARD acts analogously to a linear and fully reversible spring 111 . Molecular dynamics simulations using the NOMPC structure show that compression of the ARDs can produce a clockwise movement of the TRP domain and linker helices, similar to the TRPV1 closed-to-open gating transition 28,112 (Fig. 2e).…”

“…Force is transmitted to the channel via a tether to the extracellular matrix, the cytoskeleton or both. For example, NOMPC (middle) is tethered to microtubules via its ankyrin repeat domain (emerald) 112 . Right, the MET channel complex is tethered to the neighbouring stereocilium via the tip link (PCDH15; emerald) 16 .…”