G Proteins Are Signal Transducers

 
Many membrane receptors interact with a family of guanine nucleotide- binding proteins called G proteins. G proteins act as transducers, the agents that transmit external stimuli to effector enzymes. G proteins have GTPase activity; that is, they slowly catalyze hydrolysis of bound guanosine 5′-triphosphate (GTP, the guanine analog of ATP) to guanosine 5′-diphosphate (GDP). GDP was Monday's Molecule #27.

When GTP is bound to G protein it is active in signal transduction and when GDP is bound to G protein it is inactive. The cyclic activation and deactivation of G proteins is shown below. The G proteins involved in signaling by hormone receptors are peripheral membrane proteins located on the inner surface of the plasma membrane.

Each protein consists of an α, a β, and a γ subunit. The α and γ subunits are lipid-anchored membrane proteins; the α subunit is a fatty-acyl anchored protein, and the γ subunit is prenyl-anchored protein. The complex of G_αβγ and GDP is inactive.

When a hormone–receptor complex diffusing laterally in the membrane encounters and binds G_αβγ it induces the G protein to change to an active conformation. Bound GDP is rapidly exchanged for GTP, promoting the dissociation of G_α-GTP from G_βγ. Activated G_α-GTP then interacts with the effector enzyme. For example, it can stimulate adenylyl cyclase in regulating glycogen metabolism or in causing a sense of smell.

The GTPase activity of the G protein acts as a built-in timer since G proteins slowly catalyze the hydrolysis of GTP to GDP. When GTP is hydrolyzed the G_α-GDP complex reassociates with G_βγ and the G_αβγ-GDP complex is regenerated. G proteins have evolved into good switches but very poor catalysts, typically having a k_cat of only about 3 min^-1.

G proteins are found in dozens of signaling pathways, including the adenylyl cyclase and the inositol–phospholipid pathways. An effector enzyme can respond to stimulatory G proteins (G_s) or inhibitory G proteins (G_i). The α subunits of different G proteins are distinct, providing varying specificity, but the β and γ subunits are similar and often interchangeable. Humans have two dozen α proteins, five β proteins, and six γ proteins.