Domain swapping in G-protein coupled receptor dimers

Abstract

Computer simulations were performed on models of the beta2-adrenergic receptor dimer, including 5,6-domain swapped dimers which have been proposed as the active, high affinity form (here the dimer interface lies between helices 5 and 6). The calculations suggest that the domain swapped dimer is a high energy structure in both the apo dimer and in the presence of propranolol. In the presence of agonist the energy of the domain swapped dimer is significantly lowered. Analysis of the dimer structure suggests that the agonist-induced conformational change optimizes the helix-helix interactions at the 5-6 interface. An antagonist on the other hand has little effect on these interactions. These observations are consistent with the hypothesis that the agonist functions by shifting the equilibrium in favour of the domain swapped dimer. Indirect support for the domain swapping hypothesis was obtained from the correlated mutations amongst the external residues of the known beta2-adrenergic receptors. These occur mainly at the 5-6 interface at precisely the locations predicted by the simulations; site-directed mutagenesis data in support of a functional role for these lipid-facing correlated residues is presented. The article includes a review of the experimental evidence for G-protein coupled receptor dimerization. Many other aspects of G-protein coupled receptor activation are discussed in terms of this domain swapping hypothesis

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…Data from microscopy, covalent cross-linking, and x-ray crystallography experiments have revealed that cell surface receptors from many structural classes assemble into multi-receptor complexes; these include some heptahelical G-protein coupled receptors (GPCRs), [36][37][38] methyl-accepting chemotaxis proteins (MCPs), [39] gated ion channels, [40] receptor protein tyrosine kinases (RPTKs), [41,42] and multichain immune recognition receptors (MIRRs). [22,33,35,[43][44][45] The size of these ensembles varies: Some complexes are composed of two receptors while others contain thousands.…”

“…[49] For example, helix-mediated multimerization is proposed to mediate the dimerization and oligomerization of GPCRs (Figure 2). [38,50,51] Evidence for the functional importance of these interactions is suggested by engineering disrupting mutations in the proposed contact sites or by adding isolated transmembrane helices to GPCRs. [37,52,53] Although their effects on receptor oligomerization are not yet well-established, these manipulations modulate signaling; presumably, they disrupt receptor-receptor contacts.…”

Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation

“…Fig. 4 shows one of the proposed structural models for GPCR receptor dimers, 5,6-domain swapped dimers (Gouldson et al ., 1998). Each transmembrane alpha helix is represented as a circle.…”

Detection of beta 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET)

“…However, a growing body of functional and biochemical evidence suggests that they may exist as homo-or heterodimers. The functional evidence is based largely on positive and negative effects that dominant receptor mutants have on wild-type receptor function and on the observation that coexpression of two defective receptors can restore activity (1)(2)(3)(4)(5)(6). More recently, coexpression of the type-2b ␥-aminobutyric acid receptor GABAb-R2 was found to be essential for the cell surface expression and the function of the GABAb-R1 subtype (7)(8)(9), suggesting that heterodimerization between the two receptor molecules is required for function.…”