Cholesterol-dependent Conformational Plasticity in GPCR Dimers

Xavier Prasanna,Durba Sengupta,Amitabha Chattopadhyay

doi:10.1038/srep31858

Xavier Prasanna, Durba Sengupta + Show 1 more

Open Access

https://doi.org/10.1038/srep31858

Copy DOI

Abstract

The organization and function of the serotonin1A receptor, an important member of the GPCR family, have been shown to be cholesterol-dependent, although the molecular mechanism is not clear. We performed a comprehensive structural and dynamic analysis of dimerization of the serotonin1A receptor by coarse-grain molecular dynamics simulations totaling 3.6 ms to explore the molecular details of its cholesterol-dependent association. A major finding is that the plasticity and flexibility of the receptor dimers increase with increased cholesterol concentration. In particular, a dimer interface formed by transmembrane helices I-I was found to be sensitive to cholesterol. The modulation of dimer interface appears to arise from a combination of direct cholesterol occupancy and indirect membrane effects. Interestingly, the presence of cholesterol at the dimer interface is correlated with increased dimer plasticity and flexibility. These results represent an important step in characterizing the molecular interactions in GPCR organization with potential relevance to therapeutic interventions.

Highlights

G protein-coupled receptors (GPCRs) are lipid-dependent membrane receptors[1,2,3,4] that constitute the largest family of current therapeutic targets[5,6]
We have used coarse-grain molecular dynamics simulations to analyze the dimerization of the serotonin1A receptor in membranes of varying cholesterol content
The dimerization of membrane-embedded serotonin1A receptors was analyzed from a series of coarse-grain molecular dynamics simulations, totaling to 3.6 ms of simulation time

Summary

Introduction

G protein-coupled receptors (GPCRs) are lipid-dependent membrane receptors[1,2,3,4] that constitute the largest family of current therapeutic targets[5,6]. Receptor oligomerization assumes greater significance for better therapeutic strategies and recent exploratory studies have confirmed the increased specificity of multivalent drugs[27], as well as ligand sensitivity of the various dimer interfaces[28] In this overall context, GPCR oligomerization is an emerging paradigm, and needs to be explored in detail to improve our understanding of GPCR function in health and disease. The serotonin1A receptor serves as an important drug target for neuropsychiatric disorders such as anxiety and depression as well as in neuronal developmental defects[32] It is one of the first receptors for which cholesterol dependence of ligand binding and signaling function was demonstratedreviewed in 33–35. We postulate that increased cholesterol concentration at the interface between the two receptors, reminiscent of ‘nonannular’ sites[38], is responsible for the increased dimer rotational flexibility and plasticity These results help explain the molecular mechanism governing cholesterol-dependent receptor oligomerization. We believe these results provide an important first step toward the design of therapeutic strategies that could be exploited for tissue-specific and age-dependent interventions

Methods

Results

Conclusion