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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.

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.

References associated with 8.A.93 family:

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] 28559337
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. 28449094
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] 28645899
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. 20089882
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. 27421092
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. 27042935
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. 25422095
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. 28235766