G protein

G proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. They are so called because of their signaling mechanism, which uses the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) as a molecular "switch" to allow or inhibit biochemical reactions inside the cell. Alfred Gilman and Martin Rodbell were awarded the Nobel Prize in Physiology or Medicine in 1994 for their discovery of and research on G proteins.

General properties

G proteins belong to the larger grouping of GTPases. "G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha (α), beta (β) and gamma (γ) subunits. There are also "small" G proteins or small GTPases like Ras that are monomeric and not membrane-associated, but also bind GTP and GDP and are involved in signal transduction.

G proteins are perhaps the most important signal transducing molecules in cells. In fact, diseases such as diabetes and certain forms of pituitary cancer, among many others, are thought to have some root in the malfunction of G proteins, and thus a fundamental understanding of their function, signaling pathways, and protein interactions may lead to eventual treatments and possibly the creation of various preventive approaches.

Introduction

A common way to translate a signal to a biologic effect inside cells is by way of nucleotide regulatory proteins (G proteins) that bind GTP. GTP is the guanosine analog of ATP . When the signal reaches a G protein, the protein exchanges GDP for GTP. The GTP-protein complex brings about the effect. The inherent GTPase activity of the protein then converts GTP to GDP, restoring the resting state. The GTPase activity is accelerated by a family of RGS (regulators of G protein signaling) proteins that accelerate the formation of GDP.

Small G proteins are involved in many cellular functions. Members of the Rab family of these proteins 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, and a third family, the Ras family, regulates growth by transmitting signals from the cell membrane to the nucleus. The members of these three families are related to the product of the ras proto-oncogene.

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. These G proteins are made up of three subunits designated a, b, and g . The a subunit is bound to GDP. When a ligand binds to a G-coupled receptor, this GDP is exchanged for GTP and the a subunit separates from the combined b and g subunits. The separated a subunit brings about many biologic effects. The b and g subunits do not separate from each other, and bg also activates a variety of effectors. The intrinsic GTPase activity of the a subunit then converts GTP to GDP, and this leads to reassociation of the a with the bg subunit and termination of effector activation.

Heterotrimeric G proteins relay signals from over 1000 receptors, and their effectors in the cells include ion channels and enzymes. There are 16 a, 6 b, and 12 g genes, so a large number of subunits are produced, and they can combine in various ways. They can be divided into five families, each with a relatively characteristic set of effectors. The families are Gs, Gi, Gt, Gq, and G13.

Many G proteins are modified by having specific lipids attached to them, ie, they are lipidated . Trimeric G proteins may be myristolated, palmitoylated, or prenylated. Small G proteins may be prenylated.

Serpentine Receptors

All the heterotrimeric G protein-coupled receptors that have been characterized to date are proteins that span the cell membrane seven times (serpentine receptors). These receptors may be palmitoylated. A very large number have been cloned, and their functions are multiple and diverse. In general, small ligands bind to the amino acid residues in the membrane, whereas large polypeptide and protein ligands bind to the extracellular domains, which are bigger and better developed in the receptors for polypeptides and proteins. It is generally amino acid residues in the third cytoplasmic loop, the loop nearest the carboxyl terminal, that interact with the G proteins.

Receptor-activated G proteins

Receptor activated G proteins are bound to the inside surface of the cell membrane. They consist of the G_α and the tightly associated G_βγ subunits. When a ligand activates the G protein-coupled receptor, the G protein binds to the receptor, releases its bound GDP from the G_α subunit, and binds a new molecule of GTP. This exchange triggers the dissociation of the G_α subunit, the G_βγ dimer, and the receptor. Both, G_α-GTP and G_βγ, can then activate different signalling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein. The G_α subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to reassociate with G_βγ and starting a new cycle.

A well characterized example of a G protein-triggered signalling cascade is the cAMP pathway. The enzyme adenylate cyclase is activated by G_αs-GTP and synthesizes the second messenger cyclic adenosine monophosphate (cAMP) from ATP. Second messengers then interact with other proteins downstream to cause a change in cell behavior.

Alpha subunits

G_α subunits consist of two domains, the GTPase domain, and the alpha-helical domain. There exist at least 20 different G_α subunits, which are separated into several main families:

G_αs or simply G_s (stimulatory) - activates adenylate cyclase to increase cAMP synthesis
G_αi or simply G_i (inhibitory) - inhibits adenylate cyclase
G_olf (olfactory) - couples to olfactory receptors
G_t (transducin) - transduces visual signals in conjunction with rhodopsin in the retina
G_q - stimulates phospholipase C
The G_12/13 family - important for regulating the cytoskeleton, cell junctions, and other processes related to movements

Beta-gamma complex

The β and γ subunits are closely bound to one another and are referred to as the beta-gamma complex. The G_βγ complex is released from the G_α subunit after its GDP-GTP exchange. The free G_βγ complex can act as a signaling molecule itself, by activating other second messengers or by gating ion channels directly. For example, the G_βγ complex, when bound to histamine receptors, can activate phospholipase A₂. G_βγ complexes bound to muscarinic acetylcholine receptors, on the other hand, directly open G protein coupled inward rectifying potassium (GIRK) channels.

G protein–coupled receptors

Ligands: Epinephrine, glucagon, serotonin, vasopressin, ACTH, adenosine, and many others (mammals); odorant molecules, light; mating factors (yeast) Receptors: Seven transmembrane helices; cytosolic domain associated with a membrane-tethered trimeric G protein Signal transduction: (1) Second-messenger pathways involving cAMP or IP3/DAG; (2) linked ion channels; (3) MAP kinase pathway

References

Lodish et al. 2000. Molecular Cell Biology 4th ed. W.H. Freeman and Company, New York.
Voet, Donald and Judith G. Voet. 1995. Biochemistry 2nd ed. John Wilely & Sons, New York.

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