Oligomeric forms of G protein-coupled receptors (GPCRs)

Abstract

Oligomerization is a general characteristic of cell membrane receptors that is shared by G protein-coupled receptors (GPCRs) together with their G protein partners. Recent studies of these complexes, both in vivo and in purified reconstituted forms, unequivocally support this contention for GPCRs, perhaps with only rare exceptions. As evidence has evolved from experimental cell lines to more relevant in vivo studies and from indirect biophysical approaches to well defined isolated complexes of dimeric receptors alone and complexed with G proteins, there is an expectation that the structural basis of oligomerization and the functional consequences for membrane signaling will be elucidated. Oligomerization of cell membrane receptors is fully supported by both thermodynamic calculations and the selectivity and duration of signaling required to reach targets located in various cellular compartments.

Figure 1

In vivo dimerization of the luteinizing hormone receptor (LHR). This drawing depicts intermolecular cooperation of two molecules of the receptor. In wild-type mice (i), a signal is generated when hormone binds to the receptor and animals undergo normal gonadogenesis and are fertile. Mice with a knockout of the gene encoding LHR, or transgenic mice expressing a mutant LHR that cannot signal through G proteins because one of the transmembrane helices and two loops (residues 553–689) (ii) were eliminated, developed hypogonadism and sterility. Similarly, transgenic mice lacking the capability of binding luteinizing hormone because of mutations affecting the ectodomain (iii) also developed hypogonadism and sterility. However, when the binding- and signaling-deficient LHR mutants were cross-bred (iv), their offspring displayed partially-restored signaling and were fertile. Figure based on ,

Figure 2

Structural models of rhodopsin and its G protein. A. Atomic structure of dimeric forms of the prototypical GPCR, photoactivated rhodopsin. (i) The region above the receptor is the cytoplasmic face and below is the extracellular domain (PDB ID codes 2I35) . Helices are colored according to their primary sequence: helix-I, blue; helix-II, blue-green; helix-III, green; helix-IV, lime-green; helix-V, yellow; helix-VI, orange; helix-VII, red; cytoplasmic helix-8, purple. (ii) The cytoplasmic surface of the dimeric photoactivated rhodopsin in the crystal is shown. B. Schematic representation of the complex between photoactivated rhodopsin and Gt. Light illumination triggers structural changes in rhodopsin and promotes binding of Gt to the photoactivated rhodopsin/rhodopsin dimer. Activation of one rhodopsin subunit in the dimer is enough to induce Gt association, which stimulates GDP (green) release from the Gt nucleotide-binding pocket. This results in formation of the photoactivated rhodopsin-Gt_e complex with a free nucleotide-binding pocket. However, loading of GTP (not shown) causes complex dissociation. Photoactivated rhodopsin-Gt_e is amenable to ligand removal (all-trans-retinylidene chromophore depicted as a yellow structure) without dissociation of this complex exemplified by the empty chromophore-binding pocket and an empty nucleotide-binding pocket in opsin-Gt_e. The opsin-Gt_e complex can be regenerated with 11-cis-retinylidene (red) resulting in Rho-Gt_e complex without Gt dissociation. Only GTP breaks this complex once it is formed, suggesting high plasticity of the activated receptor and a complex that, once formed, becomes independent of the activating ligand.

Figure 3

Diversity through oligomerization. A combination of functional receptor units can include homo-oligomers of a single gene product and hetero-oligomers of multiple gene products with unique physiological/signaling properties.