G-protein

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Phosducin- transducin beta-gamma complex. Beta and gamma subunits of G-protein are shown by blue and red, respectively.

Guanosine diphosphate

Guanosine triphosphate

G proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.

G proteins are so called because they function as "molecular switches," alternating between an inactive guanosine diphosphate (GDP) and active guanosine triphosphate (GTP) bound state, ultimately going on to regulate downstream cell processes.

G proteins were discovered when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline. They found that when a hormone like adrenaline bound to a receptor, the receptor did not stimulate enzymes like adenylate cyclase directly. Instead, the receptor stimulated a G protein, which then stimulated the adenylate cyclase to produce a second messenger, cyclic AMP.^[1] For this discovery they won the 1994 Nobel Prize in Physiology or Medicine.^[2]

G proteins belong to the larger group of enzymes called GTPases.

Function

G proteins are important signal transducing molecules in cells. In fact, diseases such as diabetes, blindness, allergies, depression, cardiovascular defects and certain forms of cancer, among other pathologies, are thought to arise due to derangement of G protein signaling.

The human genomes encodes roughly 350 G protein-coupled receptors, which detect hormones, growth factors and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.

Types of G protein signaling

G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins that are activated by G protein-coupled receptors and made up of alpha (α), beta (β), and gamma (γ) subunits. There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction.

Heterotrimeric G proteins

Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformation change in the G-protein-coupled receptor, exchange GDP for GTP, and dissociate to activate other proteins in the signal transduction pathway. The specific mechanisms, however, differ among the types.

Common mechanism

Activation cycle of G-proteins by G-protein-coupled receptors

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. There are four classes of G_α subunits: G_αs, G_αi, G_αq/11, and G_α12/13. They behave differently in the recognition of the effector, but share a similar mechanism of activation.

Activation

When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP on the G_α subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the G_α subunit, bound to GTP, from the G_βγ dimer and the receptor. However, models that suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted.^[3][4] Both G_α-GTP and G_βγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.

Termination

The G_α subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with G_βγ and starting a new cycle. A group of proteins called RBMs acts as GTPase-activating proteins (GAPs), which are specific for G_α subunits, which act to accelerate hydrolysis and terminate the transduced signal. In some cases, the effector itself may possess intrinsic GAP activity, which helps deactivate the pathway. This is true in the case of phospholipase C beta, which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the G_α subunit.

Specific mechanisms

• G_αs activates the cAMP dependent pathway by stimulating the production of cAMP from ATP. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclase. cAMP acts as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can then phosphorylate a myriad of downstream targets.
• G_αi inhibits the production of cAMP from ATP.
• G_αq/11 stimulates membrane-bound phospholipase C beta, which then cleaves PIP₂ (a minor membrane phosphoinositol) into two second messengers, IP3 and diacylglycerol (DAG).
• G_α12/13 are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration.
• G_βγ sometimes also have active functions, e.g., coupling to L-type calcium channels.

Small GTPases

Small GTPases also bind GTP and GDP and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers. They are small (20-kDa to 25-kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and is also called the Ras superfamily GTPases.

Lipidation

In order to associate with the inner leaflet of the plasma membrane, many G proteins and small GTPases are lipidated, that is, covalently modified with lipid extensions. They may be myristolated, palmitoylated or prenylated.

References

1. ^ The Nobel Prize in Physiology or Medicine 1994, Illustrated Lecture.
2. ^ Press Release: The Nobel Assembly at the Karolinska Institute has today decided to award the Nobel Prize in Physiology or Medicine for 1994 jointly to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells". 10 October 1994
3. ^ Digby GJ, Lober RM, Sethi PR, Lambert NA.. "Some G protein heterotrimers physically dissociate in living cells.". Proc Natl Acad Sci USA. PMID 17095603.. 
4. ^ Khafizov K, Lattanzi G, Carloni P. "G protein inactive and active forms investigated by simulation methods". PROTEINS : Structure, Function, and Bioinformatics. PMID 19089952.. 

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