A common way to translate a signal to a biologic effect inside cells is by way of nucleotide regulatory proteins that are activated after binding GTP (G-proteins). When an activating signal reaches a G-protein, the protein exchanges GDP for GTP. The GTP–protein complex brings about the activating effect of the G-protein. The inherent GTPase activity of the protein then converts GTP to GDP, restoring the G-protein to an inactive resting state. G-proteins can be divided into two principal groups involved in cell signaling: small G-proteins and heterotrimeric G-proteins. Other groups that have simi lar regulation and are also important to cell physiology include elongation factors, dynamin, and translocation GTPases.
There are several different families of small G-proteins (or small GTPases) that are all highly regulated. GTPase activating proteins (GAPs) tend to inactivate small G-proteins by encouraging hydrolysis of GTP to GDP in the central binding site. Guanine exchange factors (GEFs) tend to activate small G-proteins by encouraging exchange of GDP for GTP in the active site. Some of the small G-proteins contain lipid modifications that help anchor them to membranes, while others are free to diffuse throughout the cytosol. Small G-proteins are involved in many cellular functions. Members of the Rab family regulate the rate of vesicle traffic between the endoplasmic reticulum, the Golgi apparatus, lysosomes, endosomes, and the cell membrane. Another family of small GTP-binding proteins, the Rho/Rac family, mediates interactions between the cytoskeleton and cell membrane. The Ras family regulates growth by transmitting signals from the cell membrane to the nucleus.
Another family of G-proteins, the larger heterotrimeric G-proteins, couple cell surface receptors to catalytic units that catalyze the intracellular formation of second messengers or couple the receptors directly to ion channels. Despite the knowledge of the small G-proteins described above, the heteromeric G-proteins are frequently referred to in the shortened “G-protein” form because they were the first to be identified. Heterotrimeric G-proteins are made up of three subunits designated α, β, and γ (Figure 1). Both the α and the γ sub units have lipid modifications that anchor these proteins to the plasma membrane. The α subunit is bound to GDP. When a ligand binds to a G-protein–coupled receptor (GPCR, dis cussed below), this GDP is exchanged for GTP and the α subunit separates from the combined β and γ subunits. The separated α subunit brings about many biologic effects. The β and γ sub units are tightly bound in the cell and together form a signaling molecule that can also activate a variety of effectors. The intrinsic GTPase activity of the α subunit then converts GTP to GDP, and this leads to reassociation of the α with the βγ sub unit and termination of effector activation. The GTPase activity of the α subunit can be accelerated by a family of regulators of G-protein signaling (RGS).
Fig1. Heterotrimeric G-proteins. Top: Summary of overall reaction that occurs in the Gα subunit. Bottom: When the ligand (red oval) binds to the G-protein–coupled receptor in the cell membrane, GTP replaces GDP on the α subunit. GTP-α separates from the βγ subunit and GTP-α and βγ both activate various effectors, producing physiologic effects. The intrinsic GTPase activity of GTP-α then converts GTP to GDP, and the α, β, and γ subunits reassociate.
Heterotrimeric G-proteins relay signals from over 1000 GPCRs, and their effectors in the cells include ion channels and enzymes. There are 20 α, 6 β, and 12 γ genes, which allow for over 1400 α, β, and γ combinations. Not all combinations occur in the cell, but over 20 different heterotrimeric G-proteins have been well documented in cell signaling. They can be divided into five families, each with a relatively characteristic set of effectors.
