Cryo-EM structures of human TMEM120A and TMEM120B

Abstract

TMEM120A (Transmembrane protein 120A) was recently identified as a mechanical pain sensing ion channel named as TACAN, while its homologue TMEM120B has no mechanosensing property1. Here, we report the cryo-EM structures of both human TMEM120A and TMEM120B. The two structures share the same dimeric assembly, mediated by extensive interactions through the transmembrane domain (TMD) and the N-terminal coiled coil domain (CCD). However, the nearly identical structures cannot provide clues for the difference in mechanosensing between TMEM120A and TMEM120B. Although TMEM120A could mediate conducting currents in a bilayer system, it does not mediate mechanical-induced currents in a heterologous expression system, suggesting TMEM120A is unlikely a mechanosensing channel. Instead, the TMDs of TMEM120A and TMEM120B resemble the structure of a fatty acid elongase, ELOVL7, indicating their potential role of an enzyme in lipid metabolism.

The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender?

“…[ 22 ] However, the mechanosensitive channel activity of TMEM120A and its role in mechanical pain sensing have recently been challenged by a flurry of recent studies, in which electrophysiological and structural experiments demonstrated that TMEM120A does not mediate mechanosensitive currents in cells and has no clear ion channel characteristics. [ 23–26 ] In addition, a recent Patch‐seq of mouse DRG (Dorsal root ganglia) neurons showed that TMEM120A is expressed in the DRG neurons but does not contribute to mechanosensitive currents in these neurons. [ 27 ] These findings strongly argue against TMEM120A as a mechanosensitive channel and suggest other functions of TMEM120A.…”

“…In 2021, four independent Cryo‐EM (Cryogenic electron microscopy) studies elucidated the struture of TMEM120A, including one study that showed that TMEM120A has almost identical structure with TMEM120B. [ 23–26 ] However, TMEM120A shares no structure similarities with known ion channels which are mechanosensitive such as Piezos. [ 23–26,29,30 ] MscL, [ 13,14 ] TRPV4 (Transient receptor potential cation channel subfamily V member 4), [ 31 ] etc.…”

“…[ 23–26 ] However, TMEM120A shares no structure similarities with known ion channels which are mechanosensitive such as Piezos. [ 23–26,29,30 ] MscL, [ 13,14 ] TRPV4 (Transient receptor potential cation channel subfamily V member 4), [ 31 ] etc. For example, Piezos form three‐bladed, propeller‐like homotrimers, whereas TMEM120A forms a seesaw rocker‐like homodimer (Figure 1A).…”

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

“…3A). According to its cryo-EM structure, membrane embedded TMEM120A has 6 transmembrane helices and forms homodimers (Ke et al, 2021;Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Intriguing, a consensus has yet to emerge regarding the subcellular localization of TMEM120A.…”

“…More recently, TMEM120A was reported to act at the cell surface as an ion channel that is sensitive to mechanical cues (Beaulieu-Laroche et al, 2020). However, four independent studies did not support such conclusion (Ke et al, 2021;Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). Instead, structural and biochemical analyses indicate that TMEM120A forms a symmetrical homodimer and each protomer binds specifically to a coenzyme-A (CoASH) molecule (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021).…”