This model  also assumes an active role of GPy in mediating GDP release, but proposes a different GDP exit pathway. As mentioned above, the helical domain caps the guanine nucleotide binding site. As in the lever-arm model, the gear shift posits that the receptor engages the N-terminal a - helix of Ga (Na in Fig. 4.2c). However, the receptor presses GPy downward; the Py dimer moves as a rigid body and it is in particular the N-terminal end of Gy (Ny in
Figure 4.2 Receptor dimerization. (a) One receptor interacts with one G protein resulting in 1:1 complex of GPCR and G protein: a single monomeric G proteincoupled receptor, represented by a GPCR such as the p2 adrenergic receptor or bovine rhodopsin monomer (shown as grey, membrane spanning Ribbon model, Protein Data Bank [PDB] ID, 2RHI361; ref. 54), interacts with a single G protein, that is, heterotri-meric transducin (shown as grey Ribbon model, PDB ID 1GOT- ref. 13), to activate the G protein and hence release GDP. This schematic rendering orients the receptor in a manner consistent with the "lever-arm" and "gear-shift" models of G protein activation. (b) Two receptors dimerize with one G protein: a GPCR dimer, indicated by the rhodopsin dimer, interacts with a single G protein (here, the transducin hetero-trimer). The receptor dimer is positioned over the G protein in a manner consistent with the "sequential fit" model of G protein activation, where one receptor engages the receptor contact sites on GPy and the second receptor triggers the C--erminal latch (note, though, that in the sequential fit model, one receptor moiety sequentially interacts with the two contact sites). (c) Two receptors and two G proteins: a GPCR dimer, indicated by the rhodopsin dimer, interacts simultaneously with two G proteins (here: heterotrimeric transducin). This model is difficult to conceptualize because the two G proteins are sterically hindered from interacting with the receptor dimer simultaneously.
Fig. 4.2c), which displaces the helical domain. Accordingly, helical and RAS-like domains are pried apart to create an exit pathway for GDP.
Switch 1 is connected to the helical domain via helix F; thus both, the lever-arm and the gear- shift models, require a movement in switch 1. Receptor-induced movements have been observed in switch 1 and switch 2 by electron spin resonance of appropriately labeled Ga^ [16,17]. The observations are consistent with a change in the mobility (decline in the mobility of switch 1 residues, ; increase in the mobility of switch 2 residues). However, the data do not allow for differentiating between these two models. Neither the lever-arm, nor the gear-shift model account for the fact that receptor-mimetic pep-tides (e.g., D2N, see below) do not require GPy or the N-terminus of Ga to activate GDP release. Similarly, it is possible to observe an—albeit inefficient —interaction between Ga and receptor in the absence of GPy [18,19]. Last, but not least, a given receptor has multiple contact sites; on GP, Gy, and the N- and C-termini as well as the on the a4/p6 segment of Ga. A glance at
Fig. 4.1a illustrates that a monomeric receptor has a foot size that is not commensurate with the shoe size of its biochemical footprint  , In other words, it appears unlikely that a (monomeric) receptor can bind all contact sites simultaneously.
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