Abstract
TMEM120A, also named as TACAN, is a novel membrane protein highly conserved in vertebrates and was recently proposed to be a mechanosensitive channel involved in sensing mechanical pain. Here we present the single-particle cryogenic electron microscopy (cryo-EM) structure of human TMEM120A, which forms a tightly packed dimer with extensive interactions mediated by the N-terminal coiled coil domain (CCD), the C-terminal transmembrane domain (TMD), and the re-entrant loop between the two domains. The TMD of each TMEM120A subunit contains six transmembrane helices (TMs) and has no clear structural feature of a channel protein. Instead, the six TMs form an α-barrel with a deep pocket where a coenzyme A (CoA) molecule is bound. Intriguingly, some structural features of TMEM120A resemble those of elongase for very long-chain fatty acids (ELOVL) despite the low sequence homology between them, pointing to the possibility that TMEM120A may function as an enzyme for fatty acid metabolism, rather than a mechanosensitive channel.
Highlights
TMEM120A was initially identified as a nuclear envelope transmembrane protein (NET) by proteomics and was originally named as NET29 (Malik et al, 2010; Schirmer et al, 2003)
While we are unable to define the physiological function of TMEM120A in this study, its structural similarity to ELOVL7 leads us to suspect that TMEM120A may function as an enzyme for lipid metabolism rather than an ion channel
Similar pressure-evoked currents were observed in both the control cells and HEK293 cells expressing TMEM120A (Figure 1a). These pressure-evoked currents were likely from the endogenous Piezo1 channel as no pressure-elicited channel activity was observed when Piezo1 knockout (P1KO) HEK293 cells were used for TMEM120A expression and recordings (Figure 1b)
Summary
TMEM120A was initially identified as a nuclear envelope transmembrane protein (NET) by proteomics and was originally named as NET29 (Malik et al, 2010; Schirmer et al, 2003). A completely different function has been proposed for TMEM120A in another recent study in which TMEM120A, renamed to TACAN, was shown to be expressed in the plasma membrane of a subset of sensory neurons and function as a mechanosensitive channel involved in sensing mechanical pain (BeaulieuLaroche et al, 2020). This finding of a potential novel mechanosensitive channel propelled us to pursue the structural and functional studies of human TMEM120A. While we are unable to define the physiological function of TMEM120A in this study, its structural similarity to ELOVL7 leads us to suspect that TMEM120A may function as an enzyme for lipid metabolism rather than an ion channel
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