8.A.93.  The Sigma2 Receptor or TMEM97 (S2R) Family 

The endoplasmic reticulum (ER) TMEM97 protein (the sigma2 or σ2 receptor) of 176 aas and 4 predicted TMSs (TC#8.A.93.1.1) has both N- and C-termini in the cytoplasm.  It has an ER targetting sequence and is an ER resident protein that regulates the sterol transporter, NPC1 (TC# 2.A.6.6.1) (Maxfield et al. 2016). It is involved in diseases as diverse as cancer and neurological disorders (Alon et al. 2017). It has been associated with cholesterol homeostasis and has been implicated in Niemann–Pick disease (Kim and Pasternak 2017). TMEM97 possesses the full suite of molecular properties that define the sigma2 receptor, and Asp29 and Asp56 are essential for ligand recognition (Alon et al. 2017). These two aspartate residues are predicted to reside near the ER luminal surface. There is a link between TMEM97 and chronic inflammation in obesity in adipose tissue and skeletal muscle (Tenta et al. 2022).

A human homologue, Tm6sf1, is present in lysosomal membranes.  Fusion of Tm6sf1 vesicles with lysosomes and the integration of Tm6sf1 into the lysosomal membrane has been demonstrated (Tam et al. 2015). The protein is expressed in mouse tissues in major organs such as the cerebellum, kidney and intestine. The sigma2R/TMEM97 small molecule modulator, JVW-1034, reduces heavy alcohol drinking and associated pain states in male mice (Quadir et al. 2020). TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3beta/beta-catenin signaling pathway (Mao et al. 2022).

There are two known subtypes of the so-called sigma receptors, Sigma1 and Sigma2. Sigma1 (encoded by the SIGMAR1 gene and also known as Sigma-1 receptor, S1R) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein that allosterically modulates the activity of its associated proteins. Sigma2, transmembrane protein 97 (TMEM97), is an integral membrane protein implicated in cellular cholesterol homeostasis, playing a role for both sigma proteins in tumor biology. A growing body of evidence supports the potential of small-molecule compounds with affinity for these proteins, putative sigma ligands, as therapeutic agents to treat cancer. These compounds inhibit cancer cell proliferation, survival, adhesion, and migration, and they suppress tumor growth, to alleviate cancer-associated pain, and to exert immunomodulatory properties (Oyer et al. 2019).


 

References:

Alon, A., H.R. Schmidt, M.D. Wood, J.J. Sahn, S.F. Martin, and A.C. Kruse. (2017). Identification of the gene that codes for the σ2 receptor. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Di Sessa, A., S. Guarino, A.P. Passaro, L. Liguori, G.R. Umano, G. Cirillo, E. Miraglia Del Giudice, and P. Marzuillo. (2021). NAFLD and renal function in children: is there a genetic link? Expert Rev Gastroenterol Hepatol 1-10. [Epub: Ahead of Print]

Ehrhardt, N., M.E. Doche, S. Chen, H.Z. Mao, M.T. Walsh, C. Bedoya, M. Guindi, W. Xiong, J. Ignatius Irudayam, J. Iqbal, S. Fuchs, S.W. French, M. Mahmood Hussain, M. Arditi, V. Arumugaswami, and M. Péterfy. (2017). Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Hum Mol Genet 26: 2719-2731.

Intagliata, S., A. Sharma, T.I. King, C. Mesangeau, M. Seminerio, F.T. Chin, L.L. Wilson, R.R. Matsumoto, J.P. McLaughlin, B.A. Avery, and C.R. McCurdy. (2020). Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo. AAPS J 22: 94.

Kim, F.J. and G.W. Pasternak. (2017). Cloning the sigma2 receptor: Wandering 40 years to find an identity. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Kim, F.J., I. Kovalyshyn, M. Burgman, C. Neilan, C.C. Chien, and G.W. Pasternak. (2010). Sigma 1 receptor modulation of G-protein-coupled receptor signaling: potentiation of opioid transduction independent from receptor binding. Mol Pharmacol 77: 695-703.

Lee, K.J., J.S. Moon, N.Y. Kim, and J.S. Ko. (2022). Effects of PNPLA3, TM6SF2 and SAMM50 on the development and severity of non-alcoholic fatty liver disease in children. Pediatr Obes 17: e12852.

Li, T.T., T.H. Li, J. Peng, B. He, L.S. Liu, D.H. Wei, Z.S. Jiang, X.L. Zheng, and Z.H. Tang. (2018). TM6SF2: A novel target for plasma lipid regulation. Atherosclerosis 268: 170-176.

Longo, M., M. Meroni, E. Paolini, V. Erconi, F. Carli, F. Fortunato, D. Ronchi, R. Piciotti, S. Sabatini, C. Macchi, A. Alisi, L. Miele, G. Soardo, G.P. Comi, L. Valenti, M. Ruscica, A.L. Fracanzani, A. Gastaldelli, and P. Dongiovanni. (2021). TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cell Mol Gastroenterol Hepatol 13: 759-788. [Epub: Ahead of Print]

Mao, D., X. Zhang, Z. Wang, G. Xu, and Y. Zhang. (2022). TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3β/β-catenin signaling pathway. Hum Cell 35: 1535-1546.

Maxfield, F.R., D.B. Iaea, and N.H. Pipalia. (2016). Role of STARD4 and NPC1 in intracellular sterol transport. Biochem. Cell Biol. 94: 499-506.

Oyer, H.M., C.M. Sanders, and F.J. Kim. (2019). Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes. Front Pharmacol 10: 1141.

Quadir, S.G., S.M. Tanino, C.D. Rohl, J.J. Sahn, E.J. Yao, L.D.R. Cruz, P. Cottone, S.F. Martin, and V. Sabino. (2020). The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice. Neuropharmacology 108409. [Epub: Ahead of Print]

Rivera-Iñiguez, I., A. Panduro, S. Roman, and K. González-Aldaco. (2022). What do we know about nutrient-based strategies targeting molecular mechanisms associated with obesity-related fatty liver disease? Ann Hepatol 28: 100874. [Epub: Ahead of Print]

Schmidt, H.R., S. Zheng, E. Gurpinar, A. Koehl, A. Manglik, and A.C. Kruse. (2016). Crystal structure of the human σ1 receptor. Nature 532: 527-530.

Tam, W.Y., L. Jiang, and K.M. Kwan. (2015). Transmembrane 6 superfamily 1 (Tm6sf1) is a novel lysosomal transmembrane protein. Protoplasma 252: 977-983.

Tenta, M., J. Eguchi, and J. Wada. (2022). Roles of Transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle. Acta Med Okayama 76: 235-245.

Thomas, J.D., C.G. Longen, H.M. Oyer, N. Chen, C.M. Maher, J.M. Salvino, B. Kania, K.N. Anderson, W.F. Ostrander, K.E. Knudsen, and F.J. Kim. (2017). Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer. Cancer Res 77: 2439-2452.

Yousuf, M.S., J.J. Sahn, E.T. David, S. Shiers, D.M. Royer, C.D. Garcia, J. Zhang, V.M. Hong, A. Ahmad, B.J. Kolber, D.J. Liebl, S.F. Martin, and T.J. Price. (2023). Validation of σ R/TMEM97 as a neuropathic pain target: Specificity, human expression and mechanism of action. bioRxiv.

Yousuf, M.S., J.J. Sahn, H. Yang, E.T. David, S. Shiers, M. Mancilla Moreno, J. Iketem, D.M. Royer, C.D. Garcia, J. Zhang, V.M. Hong, S.M. Mian, A. Ahmad, B.J. Kolber, D.J. Liebl, S.F. Martin, and T.J. Price. (2023). Highly specific σR/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response. Proc. Natl. Acad. Sci. USA 120: e2306090120.

Examples:

TC#NameOrganismal TypeExample
8.A.93.1.1

TMEM97 protein (the sigma2 receptor (sigma2R); Mac30; S2R) of 176 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement (Alon et al. 2017).  It is an ER resident protein that regulates the sterol transporter, NPC1 (TC# 2.A.6.6.1). It is involved in diseases as diverse as cancer and neurological disorders (Alon et al. 2017).  TMEM97 possesses the full suite of molecular properties that define the sigma2 receptor, and Asp29 and Asp56 are essential for ligand recognition (Alon et al. 2017). It is regulated by a number of drugs (Intagliata et al. 2020). The highly specific sigma(2)R/TMEM97 ligand, FEM-1689, alleviates neuropathic pain and inhibits the integrated stress response (Yousuf et al. 2023).

Sigma2 receptor of Homo sapiens

 
8.A.93.1.2

TMEM97 of 184 aas and 4 TMSs

TMEM97 of Gallus gallus (Chicken)

 
8.A.93.1.3

FM151 protein of 170 aas and 4 TMSs

FM151 of Naegleria gruberi (Amoeba)

 
8.A.93.1.4

TMEM97 of 167 aas and 4 TMSs

TMEM97 of Acanthamoeba castellanii

 
Examples:

TC#NameOrganismal TypeExample
8.A.93.2.1

Transmembrane 6 superfamily 2 (TM6SF2) of 377 aas and 9 or 10 TMSs; it regulates plasma lipids. TM6SF2 variants are associated with plasma lipid traits, cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) (Li et al. 2018). The mechanisms underlying TM6SF2 regulation of lipid metabolism, involving intestinal cholesterol absorption and hepatic cholesterol biosynthesis and transport, have been discussed (Li et al. 2018). It may be involved in nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) (Di Sessa et al. 2021); Longo et al. 2021). TM6SF2 and SAMM50 are associated with the development and severity of pediatric NAFLD. The impact of genetic variants is greater in overweight children. Four genetic variants have synergetic effects on the severity of pediatric NAFLD (Lee et al. 2022). Genetic polymorphisms in TM6SF2 predispose organisms to a higher risk of liver diseases (Rivera-Iñiguez et al. 2022). It  regulates uptake of sterols via NPC1 (TC# 2.A.6.6.1) and is a neuropathic pain target (Yousuf et al. 2023).

TM6SF2 of Homo sapiens

 
8.A.93.2.2

TM6SF1 family member of 381 aas and 9 TMSs

TM6SF1 protein of Strongylocentrotus purpuratus (Purple sea urchin)

 
8.A.93.2.3

Uncharacterized TC6SF1 protein of 370 aas and 9 TMSs

UP of Sarcophilus harrisii (Tasmanian devil) (Sarcophilus laniarius)

 
8.A.93.2.4

The TM6sf1 protein of 377 aas and 9 or 10 TMSs.  Deficiency or overexpression in the liver affects ApoB trafficking and plasma lipid levels, diminished hepatic triglycerides secretion, increased hepatic stestosis and affects atherosclerosis (Ehrhardt et al. 2017).

TM6SF1 of Homo sapiens