Asymmetric Dynamics Between the Protomers of the σ2 Receptor Homodimer

TL;DR

This study reveals that the sigma-2 receptor homodimer has asymmetric movements between its two parts, which could explain how it functions and responds to ligands like cholesterol.

Contribution

The study identifies anticorrelated helical motions and salt bridge switching as drivers of asymmetric dynamics in the sigma-2 receptor homodimer.

Findings

Asymmetric dynamics in the σ2R homodimer are driven by anticorrelated helical motions and salt bridge switching.

Cholesterol binding enhances protomer asymmetry by stabilizing one subunit and altering the other's dynamics.

Species-specific allosteric interactions and asymmetric membrane coupling are observed in the bound state.

Abstract

The sigma-2 receptor (σ2R/TMEM97) is
a clinically
relevant membrane protein involved in cholesterol regulation and overexpressed
in cancer and neurodegenerative diseases. Despite its therapeutic
potential, the dynamic mechanisms underlying σ2R
function and ligand binding remain poorly understood. Here, we combined
adaptive sampling molecular dynamics simulations with quasi-anharmonic
analysis and unsupervised machine learning method to investigate the
conformational behavior of the σ2R homodimer in both
apo and cholesterol-bound states. Our results reveal asymmetric dynamics
between the two protomers. This asymmetry is driven by anticorrelated
helical motions and mutually exclusive salt bridge formation, including
a switching mechanism between K55–E139 and D122–R140. Cholesterol binding
further enhances this asymmetry by stabilizing one protomer and altering
the dynamics of the other. Species-specific allosteric interaction
between D56–R133 may be essential for
the human σ2R function. Additional lipid–protein
interaction analysis highlights asymmetric membrane coupling in the
bound state. These findings provide a plausible explanation for the
receptor’s dimeric nature, suggesting that ligand binding at
one site may allosterically influence the apo protomer, thereby modulating
receptor function. Our work provides new mechanistic insight into
σ2R function and highlights the importance of asymmetric
dynamics.

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