Electron cryo-microscopy structure of the mechanotransduction channel NOMPC

Abstract

Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells1. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the case of bacterial MscL channel and certain eukaryotic potassium channels2-5. The other is the tether model: force is transmitted via a tether to gate the channel. Recent study suggests that NOMPC, a mechanotransduction channel that mediates hearing and touch sensation in Drosophila, is gated by tethering of its ankyrin repeat (AR) domain to microtubules of the cytoskeleton6. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of force induced gating, which could serve as a paradigm of the tether model. NOMPC, a Transient Receptor Potential (TRP) channel and the founding member of the TRPN sub-family7, fulfills all the criteria for a bona fide mechanotransduction channel1,8, and is important for a variety of mechanosensation-related behaviors such as locomotion, touch and sound sensation across different species including C. elegans9, Drosophila8,10-11 and zebrafish12. NOMPC has 29 ARs, the largest number among TRP channels. They are implicated as tether to convey force from cytoskeleton to the channel, thus to mediate mechanosensation6,13-15. A key question is how the long AR domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of NOMPC determined by single particle electron cryo-microscopy (cryo-EM), and discuss how its architecture could provide a means to convey mechanical force to generating an electrical signal within a cell.

Structures of the calcium-activated, non-selective cation channel TRPM4

“…1b). The middle tier LHD has a similar structural arrangement to the linker helices of NOMPC, a mechanosensitive drosophila TRPN channel 32 . LHD barely contributes to the tetrameric assembly, but it provides the hub for multiple inter-domain interactions within the subunit and likely mediates the coupling between the bottom tier NBD/ARD tetramer assembly and the top tier transmembrane domain (Extended Data Fig.…”

“…TRP helix 2 and the loop between the two TRP helices are buried in the lower leaflet of the membrane; the loop also participates in the formation of the cavity with S1-S4 by patching the side opening. The TRP helix 2 is not present in TRPV or TRPA channel structures but was observed in NOMPC 32,42,43 .…”

Microtubule Acetylation Is Required for Mechanosensation in Drosophila

“…In the force from lipids model, plasma membrane deformation generates the tension required for channel gating via direct interaction between the mechanoreceptor and lipids of the plasma membrane (Christensen and Corey, 2007; Kung, 2005). In the force from filaments model, the channel is tethered to a non-compliant structure by a gating spring, and movement of the membrane-bound channel relative to the immobile structure induces tension within the spring to open the channel (Howard and Hudspeth, 1987; Jin et al, 2017; Liang et al, 2013). In this model, the gating spring is an elastic tether that connects the channel to extracellular structures, such as the extracellular matrix, or intracellular components, such as the cytoskeleton (Jin et al, 2017).…”

Electron cryomicroscopy as a powerful tool in biomedical research

“…Many structures were determined for a large number of medically important channels and transporters that are closely linked to various diseases [63–65]. In addition, extraordinarily large membrane protein complexes, in particular those ones involved in respiration and photosynthesis, were structurally characterized by cryo-EM [66, 67].…”