1.A.119 The Stress-inducible Transmembrane Protein, TMPIT1, TACAN or TMEM120A (TMPIT1) Family
A drought stress-inducible putative membrane protein was cloned from root tissue of wild emmer wheat. TMPIT1, is a member of the widespread but uncharacterised TMPIT (transmembrane protein inducible by TNF-α) family. The TdicTMPIT1 gene is upregulated on drought stress in drought-tolerant wild emmer wheat, but not in a drought-sensitive accession or in cultivated durum wheat. The TdicTMPIT1 product is a membrane protein with four transmembrane helices.
Human Tmem120A and Tmem120B, nuclear membrane proteins, are found in fat cells, and both are induced during 3T3-L1 adipocyte differentiation. Knockdown of one or the other protein alters expression of several genes required for adipocyte differentiation. The double knockdown increased the strength of the effects, reducing, for example, Glut4 levels by 95% upon pharmacologically induced differentiation. The TMEM120A and B fat-specific nuclear envelope transmembrane proteins may play a contributory role in the tissue-specific pathologies (Batrakou et al. 2015).
Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying essential physiological functions such as touch and pain sensing, hearing, and proprioception. Beaulieu-Laroche et al. 2020 reported the identification of TACAN (Tmem120A), an ion channel involved in sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. A nociceptor-specific inducible knockout of TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to painful mechanical stimuli but not to thermal or touch stimuli. Beaulieu-Laroche et al. 2020 proposed that TACAN is an ion channel that contributes to sensing mechanical pain.
The generalized transport reaction catalyzed by members of the TMPIT family is:
ions (out) ⇋ ions (in)
The drought stress-inducible putative membrane protein, TMPIT1
TMPIT1 of Triticum dicoccoides (G0ZL54)
Uncharacterized protein of 124 aas and 2 TMSs. This could be a fragment.
UP of an archaeon (phyllosphere metagenome)
Uncharacterized protein of 409 aas and 7 TMSs.
UP of Chlorella variabilis
Uncharacterized protein of 325 aas and 5 TMSs in a 2 + 1 + 2 TMS arrangement.
UP of Reticulomyxa filosa
The TMEM120A or TACAN protein of 343 aas and 7 TMSs. It may function in adipogenesis (Batrakou et al. 2015). TACAN is reported to be a Ca2+-transporting ion channel involved in sensing mechanical pain. It is expressed in a subset of nociceptors in humans, and its heterologous expression increases mechanically evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel that transports Ca2+ (Beaulieu-Laroche et al. 2020). However, Niu et al. 2021 failed to detect the proposed mechanosensitive ion channel activity of TACAN. Using membrane reconstitution methods, they found that TACAN, at high protein concentrations, produces heterogeneous conduction levels that are not mechanosensitive and are most consistent with disruptions of the lipid bilayer. They determined the structure of TACAN using single-particle cryo-EM and observed that it is a symmetrical dimeric transmembrane protein. Each protomer contains an intracellular-facing cleft with a coenzyme A cofactor, confirmed by mass spectrometry. The TACAN protomer is related in three-dimensional structure to a fatty acid elongase, ELOVL7. Thus, TACAN may not be a mechanosensitive ion channel. It may not mediate poking- or stretch-induced channel activities (Rong et al. 2021; Xue et al. 2021). TMEM120A genome organisation functions affect many adipose functions, and its loss may yield adiposity spectrum disorders, including an miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy (Czapiewski et al. 2022). TACAN is an ion channel-like protein that may be involved in sensing mechanical pain. Chen et al. 2022 presented the cryo-EM structure of human TACAN (hTACAN). It forms a dimer in which each protomer consists of a transmembrane globular domain (TMD) containing six helices and an intracellular domain (ICD) containing two helices. Molecular dynamic simulations suggest that each protomer contains a putative ion conduction pore. A single-point mutation of the key residue Met207 greatly increases membrane pressure-activated currents, and each hTACAN subunit binds one cholesterol molecule. The wild-type hTACAN may be in a closed state (Chen et al. 2022). TMEM120A can detect mechanical pain stimuli as a mechanosensitive channel, contributes to adipocyte differentiation/functions by regulating genome organization and promotes STING trafficking to active cellular innate immune responses (Qian et al. 2022). These multiple proposed functions of TMEM120A have been reviewed and a molecular mechanism underlying TMEM120A's role in fatty acid metabolism and STING signaling has been proposed (Qian et al. 2022). See also TC# 1.A.5.2.1. TMEM120A/TACAN has been reported to be a regulator of ion channels, mechanosensation, and lipid metabolism (Gabrielle and Rohacs 2023).
TACAN of Homo sapiens
TACAN-like protein (homologue) of 199 aas and 7 TMSs
TACAN of Arabidopsis thaliana (thale cress)
Uncharacterized protein of 113 aas and 2 TMSs. This protein corresponds to the last two TMSs in 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence.
UP of Schistosoma curassoni
Uncharacterized protein of 105 aas and 2 TMSs. This protein corresponds to the last two TMSs of the protein listed under TC# 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence.
UP of Dibothriocephalus latus
Uncharacterized protein of 131 aas and 2 TMSs. This protein corresponds to the last two TMSs of the protein with TC# 1.A.119.1.2. It could be a short version of the latter protein, or it could be an incomplete sequence. However, there seem to be multiple versions of this short protein (see TC#s 1.A.119.1.4, 1.5, and 1.6) suggesting that it may be a full-length protein. Also, the two N-terminal TMSs are followed in this protein by a hydrophilic region not present in the other homologues.
UP of Nippostrongylus brasiliensis
Uncharacterized protein of 268 aas with two C-terminal TMSs and a long hydrophilic N-terminal domain. The C-terminus is very similar to that of TC# 1.A.119 .1.5.
UP of Schistocephalus solidus
TMPIT-like protein of 355 aas and 7 TMSs
TMPIT protein of Dunaliella salina
Transmembrane 120-like protein of 747 aas and 8 probable TMSs in the central part of the protein.
TMEM120 of Chlorella sorokiniana