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.