Dynamic tuneable G protein-coupled receptor monomer-dimer populations

Abstract

G protein-coupled receptors (GPCRs) are the largest class of membrane receptors, playing a key role in the regulation of processes as varied as neurotransmission and immune response. Evidence for GPCR oligomerisation has been accumulating that challenges the idea that GPCRs function solely as monomeric receptors; however, GPCR oligomerisation remains controversial primarily due to the difficulties in comparing evidence from very different types of structural and dynamic data. Using a combination of single-molecule and ensemble FRET, double electron–electron resonance spectroscopy, and simulations, we show that dimerisation of the GPCR neurotensin receptor 1 is regulated by receptor density and is dynamically tuneable over the physiological range. We propose a “rolling dimer” interface model in which multiple dimer conformations co-exist and interconvert. These findings unite previous seemingly conflicting observations, provide a compelling mechanism for regulating receptor signalling, and act as a guide for future physiological studies.

Regulation of G protein‐coupled receptor signaling by plasma membrane organization and endocytosis

“…The β1‐adrenergic receptor (B1AR) exists predominantly as a monomer at the plasma membrane and the closely related β2‐adrenergic receptor splits its time roughly equally between monomeric and dimeric states . Receptor oligomerization is highly dynamic at physiological concentrations of receptor, as demonstrated by recent studies with the neurotensin receptor NTSR1 and rhodopsin . Changes in diffusion rate may serve to change receptor‐effector coupling, and GPCR‐G protein complexes appear to diffuse much more rapidly than GPCRs alone …”

7-Transmembrane Helical (7TMH) Proteins: Pseudo-Symmetry and Conformational Plasticity

“…Effectively, the same principle of symmetric dimerization used in sampling symmetric interfaces between protodomains ( Figure 4.C ) can be applied at the domain level to explain observed dimers in GPCRs. In fact, dynamic rotating symmetric dimers have recently been observed in GPCRs (Dijkman et al, 2018;Xue et al, 2015). Figure 4.D shows two rotating dimers synchronized on rotation to maintain a symmetric organization sampling of homodimers, which has been observed in multiple GPCR crystal structures (Dijkman et al, 2018;Xue et al, 2015).…”

“…The C2 symmetry represents the vast majority of symmetric structures with~32000 representatives, of which~31000 are homodimers. What makes GPCR dimers so special is their ability to form dynamic symmetric dimers of variable geometry, where dimeric states or conformations have been shown to be sampled during the lifetime of the dimer (Dijkman et al, 2018).…”

Structural insights into melatonin receptors

“…Strikingly, a cluster of variants is found in TM1 (P36S, A42P, A52T, and L60R) and TM2 (P95L, of the YPYP motif) (Fig. ), one of the proposed interfaces for the formation of dimers in other receptors . Recently, GPCR dimerization interfaces have been proposed to contain multiple epitopes and dynamically interconvert between different dimer conformations (‘rolling dimer’ model) , indicating that the existence of one relevant interface does not preclude the existence of another (see below).…”