Abstract
The sigma-1 receptor (S1R) is a ligand-regulated membrane protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 binding immunoglobulin protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198-206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide binding domain of BiP, but not the substrate binding domain, suggesting that the nucleotide binding domain is sufficient for S1R interactions.
Highlights
Sigma-1 receptor is a ligand-regulated membrane protein chaperone involved in binding immunoglobulin protein (BiP) regulation and the ER stress response
The sigma-1 receptor (S1R)3 is a ligand-regulated membrane protein chaperone involved in the ER stress response and interorganelle communication [1,2,3]
Chaperone activity and BiP binding [1] and the interaction of S1R with inositol triphosphate receptor [14] have been localized to the C-terminal domain of S1R, and truncation of the C terminus leads to dysfunction in mitochondrial stress response [15]
Summary
Sigma-1 receptor is a ligand-regulated membrane protein chaperone involved in BiP regulation and the ER stress response. The sigma-1 receptor (S1R) is a ligand-regulated membrane protein chaperone involved in the ER stress response. S1R has been shown previously to regulate the Hsp binding immunoglobulin protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. Chaperone activity and BiP binding [1] and the interaction of S1R with inositol triphosphate receptor [14] have been localized to the C-terminal domain of S1R, and truncation of the C terminus leads to dysfunction in mitochondrial stress response [15]. Three of the helices in the C-terminal membrane-associated domain correspond closely to regions previously implicated in cholesterol and drug interactions
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