How and why do GPCRs dimerize?

Abstract

Dimerization is fairly common in the G-protein-coupled receptor (GPCR) superfamily. First attempts to rationalize this phenomenon gave rise to an idea that two receptors in a dimer could be necessary to bind a single molecule of G protein or arrestin. Although GPCRs, G proteins and arrestins were crystallized only in their inactive conformations (in which they do not interact), the structures appeared temptingly compatible with this beautiful model. However, it did not survive the rigors of experimental testing: several recent studies unambiguously demonstrated that one receptor molecule is sufficient to activate a G protein and bind arrestin. Thus, to figure out the biological role of receptor self-association we must focus on other functions of GPCRs at different stages of their functional cycle.

Figure I

Structural elements of GPCRs and their arrangement in different receptors.

Figure I

To activate the receptor, ligand binding must change HD conformation.

Figure 1

Receptor coupling to G proteins. (a) The traditional model of one heterotrimeric G protein interacting with one active (red) receptor [9]. (b) A single HD in active conformation (red) in a dimeric receptor (a heterodimeric GABA_B receptor is shown as an example; in this receptor VFT of the GB1 subunit binds GABA, whereas the HD of the GB2 subunit couples to G proteins) is strongly supported by the evidence obtained in strictly controlled experiments [–, –40]. (c) G-protein coupling to a dimeric receptor appears to be less efficient [25,38]; it works better when one of the receptors is inactive (green) [36], as shown here. Note that a pentameric complex of two receptors with one G protein described for the leukotriene receptor B₄ [70] is equally consistent with this arrangement and with that shown in panel (d). (d) A model in which one G protein simultaneously docks to both receptors in a dimer [10] was proposed on the basis of crystal structures of an inactive receptor and an inactive (in a complex with GDP) heterotrimeric G protein, although the two proteins in these conformations do not interact. Several recent studies [–40] convincingly ruled out the idea that the receptor dimer is required for G-protein coupling. A similar two-to-one model proposed for receptor–arrestin interaction [10] was also ruled out by the demonstration that each receptor molecule binds its own arrestin [49,52]. However, it is still unclear whether arrestin (like G proteins) binds monomeric receptors better, prefers a dimer or does not care one way or the other.