TMEM97
Description
The TMEM97 (transmembrane protein 97) is a protein-coding gene located on chromosome 17.
The sigma-2 receptor (σ2R), encoded by the TMEM97 gene, is a sigma receptor subtype implicated in various diseases, including neurological diseases, neurodegenerative, neuro-ophthalmic and cancer. It is being investigated for its potential diagnostic and therapeutic uses. Although identified as a separate entity from the sigma-1 receptor in 1990, the gene coding for the receptor, TMEM97, was only discovered in 2017. TMEM97 was shown to regulate the cholesterol transporter NPC1 and to be involved in cholesterol homeostasis. The sigma-2 receptor is a four-pass transmembrane protein located in the endoplasmic reticulum. It plays a role in hormone signaling and calcium signaling, neuronal signaling, cell proliferation and death, and binding of antipsychotics. The sigma-2 receptor is located in the lipid raft and is found in several areas of the brain, including high densities in the cerebellum, motor cortex, hippocampus, and substantia nigra. It is also highly expressed in the lungs, liver, and kidneys. TMEM97 plays a role in cholesterol homeostasis.
The protein encoded by the TMEM97 gene, also known as the sigma-2 receptor, contributes to the regulation of cellular processes, potentially slowing down degenerative progression. This protein regulates cholesterol biosynthesis and trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. It forms a complex with PGRMC1 receptor and low density lipoprotein receptor/LDLR at the plasma membrane, enhancing LDL cholesterol internalization. TMEM97 decreases lysosomal sterol transporter NPC1 availability to the cell, controlling lipid transport, including cholesterol and LBPA. TMEM97 binds the ligand 20(S)-hydroxycholesterol (20(S)-OHC) which strengthens its interaction with NPC1, while weakening its interactions with PGRMC1 and TSPO, linking OHC binding to cholesterol homeostasis. TMEM97 can also bind cholesterol. It interacts with histatin 1 (Hst 1)/HN1 salivary peptide at the ER membrane, promoting mitochondrial-ER contacts and stimulating Hst1 wound healing properties. TMEM97 may alter the activity of some cytochrome P450 proteins. Despite its homology to sterol isomerases, TMEM97 is not capable of catalyzing sterol isomerization. However, it may act as a sensor of these molecules. This protein acts as a quality control factor in the ER, promoting the degradation of nonproductive and extramitochondrial precursor proteins in the ER membrane, removing them from the ER surface. It can form homodimers. TMEM97 interacts with NPC1, impairing NPC1-mediated cholesterol transport. It interacts with PGRMC1 and LDLR, increasing LDL internalization. It also interacts with histatin 1/HTN1, inducing HTN1-stimulating wound healing and with TSPO.
TMEM97 is also known as MAC30, S2R, sigma2R.
