3.2 Trimeric G proteins

G proteins are attached to the cytosolic face of the plasma membrane, where they serve as relay proteins between the receptors and their target signalling proteins.

Trimeric G proteins interact with 7TM receptors and are all heterotrimeric, having structurally different α, β and γ subunits. Monomeric G proteins are the small G proteins, such as Ras, which are structurally related to the α subunit of trimeric G proteins.

The three-dimensional structure of trimeric G proteins in their inactive form is shown in Figure 28.

Figure 28 (a) Schematic diagram of a trimeric G protein, bound to GDP, associated with the plasma membrane. (b) Three-dimensional structure of the α, β and γ subunits of a trimeric G protein. The α subunit (left, cyan) has a molecule of GDP bound, and the N-terminal helix is at the top right. The β and γ subunits (β green, γ yellow) are in close apposition forming a complex. The hydrophobic attachments that are responsible for the association of the three subunits are not shown. They involve the N-terminus of the α subunit and the C-terminus of the γ subunit. The separate βg complex on the right has been rotated about a vertical axis.(Based on pdb file 1gp2.)

Ligand binding induces a conformational change in the 7TM receptor, which results in the release of GDP and binding of GTP to the α subunit (Figure 29). As a result, the α subunit also changes conformation and becomes activated. This conformational change results in the dissociation of the α subunit from the βγ complex, which also becomes activated, although it does not change conformation itself. The α subunit primarily, and also the βγ complex to a lesser extent, regulate the activity of downstream effector proteins located on the plasma membrane. There are many different α subunits, which can be classified according to sequence similarity, and to which upstream and downstream proteins they interact with (see Table 2 for the most important ones). In fact, the G protein complex is often categorized by the type of α subunit it is formed from; hence you will come across Gα_s, Gα_i, Gα_q, etc. For example, Gα_s stimulates adenylyl cyclase, whereas Gα_i inhibits it, and Gα_q activates PLC-β (see Table 2). There are also different βγ subunits, some of which have been shown to have their own effector function. More generally, though, βγ subunits are thought to stabilize the inactive state of the α subunit.

Figure 29 Signalling through G protein-coupled receptors (GPCRs). (a) All components of the signalling pathway are shown in their inactive form. (b) The change in conformation of the 7TM receptor on ligand binding brings about the binding of the trimeric G protein. (c) GTP binds and activates the α subunit, which becomes dissociated from the βγ complex. (d) The α subunit binds and activates target proteins, which also act as effectors and propagate the signal. (e) Inactivation of the α subunit via GTPase activity (intrinsic or accessory) results in dissociation from the target protein (which itself becomes inactivated) and formation of the inactive trimeric G protein complex by association with a βγ complex (a).

G proteins usually remain active for only a short time, which depends mainly on the rate of hydrolysis of GTP to GDP (Figure 29). The intrinsic GTPase activity of the a subunit is quite inefficient by itself. For many cell signalling processes where a rapid turnover rate is necessary (for example, transduction of a photoreceptor activated by visual stimuli), the intrinsic GTPase activity of the α subunit is usually aided by binding of a second protein that enhances the rate of G protein inactivation. This may be either its target protein, ensuring that the α subunit remains active for just as long as it takes to make contact with the target, or a GTPase activating protein (GAP, Section 1.6).