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Int J Mol Sci
2023 Aug 19;2416:. doi: 10.3390/ijms241612980.
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Structure-Based Modeling of Sigma 1 Receptor Interactions with Ligands and Cholesterol and Implications for Its Biological Function.
Kim M
,
Bezprozvanny I
.
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The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. Despite its importance in physiology and disease, the biological function of S1R is poorly understood. To gain insight into the biological and signaling functions of S1R, we took advantage of recently reported crystal structures of human and Xenopus S1Rs and performed structural modeling of S1R interactions with ligands and cholesterol in the presence of the membrane. By combining bioinformatics analysis of S1R sequence and structural modelling approaches, we proposed a model that suggests that S1R may exist in two distinct conformations-"dynamic monomer" (DM) and "anchored monomer" (AM). We further propose that equilibrium between AM and DM conformations of S1R is essential for its biological function in cells, with AM conformation facilitating the oligomerization of S1R and DM conformation facilitating deoligomerization. Consistent with experimental evidence, our hypothesis predicts that increased levels of membrane cholesterol and S1R antagonists should promote the oligomeric state of S1R, but S1R agonists and pathogenic mutations should promote its deoligomerization. Obtained results provide mechanistic insights into signaling functions of S1R in cells, and the proposed model may help to explain neuroprotective effects of S1R modulators.
Figure 1. Primary sequence and secondary structure elements of S1R. (A) Complete primary sequence of human S1R (hS1R) is shown. Secondary structure elements—H1–H5 α helices and B1–B10 β-strands are labeled based on 5HK1 structural file (hS1R bound to PD144418) [24]. Alpha helices in crystal structure are labeled in grey, B1-B2 β strands are labeled in yellow, and B3-B10 β-strands are labeled in red. W9 and W11 residues predicted to form cholesterol binding site [20] are shown with a red font. The position of E102 residue mutated in ALS16 [7] is labeled red. (B) Results of PSIPRED analysis of hS1R primary sequence. Ordered probability (OD) is plotted for each amino acid (open blue circles and line). Secondary structure elements from the crystal structure [24] are shown above the OD plot. Position of E102 residue mutated in ALS16 [7] is shown by a red circle.
Figure 2. Structural model of S1R association with cholesterol in the membrane. (A) Sequence alignment of the cholesterol-binding site from SLC6A4 [36] and tandem putative cholesterol-binding sites (CARC motifs) from S1R [20]. The residues directly involved in interactions with cholesterol in SLC6A4 and predicted to interact with cholesterol on S1R are colored red. (B) Structural models of S1R with one or two cholesterol molecules bound. The residues directly involved in interactions with cholesterol in the models are colored red. Cholesterol molecules are shown by yellow. The predicted membrane boundaries are shown by the blue lines and the transparent space between the lines. (C) Anchored models of H1 α-helix from S1R. The models are shown for S1R in the absence of cholesterol (white), with one CHO bound (green), with two CHO bound (yellow), and for WWLL mutant (blue). The predicted membrane boundaries are shown by the blue lines and the transparent space between the lines.
Figure 3. Structural model of E102Q effects on S1R association with the membrane. (A) Structural models of wild type hS1R (white) and hS1R-E102Q mutant (orange) are compared. The membrane boundary is shown by the orange line. The blue arrows indicate the displacement of H4/5 and H1 α-helices in hS1R-E102Q mutant structure. (B) EM calculations for H1, BIND and H4/5 domains for wild type hS1R (blue circles) and hS1R-E102Q mutant (red circles).
Figure 4. Analysis of ligand-binding site of S1R. (A) Results of PSIPRED analysis of a portion of hS1R primary sequence that includes the ligand-binding site (P75–P223). Ordered probability (OD) is plotted for each amino acid (open blue circles and line). Secondary structure elements from the crystal structure [24] shown for the corresponding region of S1R below the OD plot. Position of E102 residue mutated in ALS16 [7] is shown by a red circle. The boundaries of regions involved in interaction with agonist (green) and antagonists (yellow) are shown by bars below the OD plot. (B) Overlay of fragments of the hS1R structures with 4 antagonists (all shown in yellow) from 5HK1 (hS1R bound to PD144418) [24], 5HK2 (hS1R receptor bound to 4-IBP) [24], 6DK0 (hS1R bound to NE-100) [25], 6DJZ (hS1R bound to haloperidol) [25] and agonist (shown in green) 6DK1 (hS1R bound to (+)-pentazocine) [25]. (C) Overlay of fragments of the xS1R structures with antagonist (shown in yellow) 7W2F (xS1R bound to PRE084) [26] and agonist (shown in green) 7W2D (xS1R bound to S1RA) [26]. On panels B and C, B2 β-strand is shown in orange and H4/H5 α-helices are shown in blue.
Figure 5. Proposed conformational equilibrium of S1R. (A) Schematic depiction of dynamic monomer (DM) conformation and anchored monomer (AM) conformations of S1R. Possible movements of H1 α-helix (m1), H4/5 α-helices (m2) and unfolding of BIND domain (m3) are shown. The equilibrium between DM and AM conformations is affected by S1R agonists, S1R antagonists, cholesterol (CHO) in the membrane and E102Q pathogenic mutation, as shown. (B) Proposed distribution of different S1R conformations. AM conformation is well defined and forms a narrow peak in conformational space. DM conformation is a spectrum of molecular species that differ from each other in the tilt of H1 α-helix, position of H4/5 α-helices relative to the surface of the membrane and the folding state of BIND domain. As a result, DM conformation forms a broad peak in conformational space.
Figure 6. Proposed mechanism of S1R oligomerization. (A) S1R in the AM monomeric form promotes the generation of large oligomers due to the formation of BIND-BIND trimers and H1-H1 dimers. Large oligomers are stabilized in the presence of cholesterol (CHO) or S1R antagonists. (B) S1R agonists cause the conversion of AM conformation of S1R to DM conformation resulting in a loss of BIND-BIND and H1-H1 intramolecular associations and the disassembly of large S1R oligomers and clusters.
Supplementary Figure S1. Structural model of E102Q effects on S1R association with the membrane in the presence of bound NE-100.
Structure of wild type hS1R bound to NE100 (white) from PDB file 6DK0. E102Q mutation was introduced by Coot and resulting effects on membrane association was calculated by EMBEDED. Predicted conformation of hS1R-E102Q in complex with NE-100 is shown (orange).
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