Crystal structure of the human σ1 receptor

Abstract

The human σ1 receptor is an enigmatic ER-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain1. Recently, an additional connection to amyotrophic lateral sclerosis (ALS) has emerged from studies of human genetics and mouse models2. Unlike many transmembrane receptors that belong to large, extensively studied families such as G protein-coupled receptors or ligand-gated ion channels, the σ1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the σ1 receptor and its regulation by drug-like compounds remain poorly defined. Here, we report crystal structures of the human σ1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the ER membrane in cells. This domain includes a cupin-like β-barrel with the ligand-binding site buried at its center. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein.

Aberrant Subcellular Dynamics of Sigma-1 Receptor Mutants Underlying Neuromuscular Diseases

“…Deletion of amino acids 31-50 in s-1R-D31-50 resulted in a diffused distribution pattern throughout the entire cell with high mobility resembling a soluble cytosolic protein. This finding was unexpected given that the crystal structure of the s-1R has residues 31-50 assembling in a cytosolic, predominantly a-helical domain (Schmidt et al, 2016). This is on the opposite side of the ER membrane to the presumed double arginine ER-retention motif (Schutze et al, 1994;Hanner et al, 1996).…”

“…3, A and B). This distribution is reminiscent of a soluble protein, which was unexpected as the transmembrane domain remains intact and amino acid residues 31-50 are not part of a predicted ER retention sequence (Brune et al, 2013;Schmidt et al, 2016).…”

“…A single missense mutation in the second exon of the SIGMAR1 gene is associated with a juvenile form of ALS (ALS16; Al-Saif et al, 2011). This mutation results in a substitution of glutamine for glutamic acid at position 102 (E102Q) located in the linker region between b2 and b3, which form the base of the ligandbinding b-barrel (Schmidt et al, 2016). Another SIGMAR1 gene mutation (c15111G.T) has been identified in a consanguineous Chinese family (Li et al, 2015).…”

“…Another SIGMAR1 gene mutation (c15111G.T) has been identified in a consanguineous Chinese family (Li et al, 2015). This mutation leads to an in-frame deletion of 60 base pairs in exon one, generating a s-1R that lacks the a2 helix encoded by amino acids 31-50 (Schmidt et al, 2016). Expression of this shortened s-1R variant results in a dHMN phenotype characterized by significant muscle atrophy (Li et al, 2015).…”

“…The s-1R is a highly evolutionarily conserved, 223 amino acid mammalian protein consisting of a single transmembrane domain (Schmidt et al, 2016). A single missense mutation in the second exon of the SIGMAR1 gene is associated with a juvenile form of ALS (ALS16; Al-Saif et al, 2011).…”