Identification of the gene that codes for the σ2 receptor

The sigma(2) receptor is an enigmatic protein that has attracted significant attention because of its involvement in diseases as diverse as cancer and neurological disorders. Unlike virtually all other receptors of medical interest, it has eluded molecular cloning since its discovery, and the gene that codes for the receptor remains unknown, precluding the use of modern biological methods to study its function. Using a chemical biology approach, we purified the sigma(2) receptor from tissue, revealing its identity as TMEM97, an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter NPC1. We show that TMEM97 possesses the full suite of molecular properties that define the sigma(2) receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the sigma(2) receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target.