G protein

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3D structure of a heterotrimeric G protein

An heterotrimeric G protein. GDP is in purple. Alpha chain in orange. Beta chain in blue. Gamma chain in green. An important loop for signal transduction is shown in red (PDB code=1gg2) (more details...)

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 general molecular "switch" function to regulate cell processes. 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.

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.

G proteins belong to the larger grouping of GTPases.

[edit] Large and small G proteins

• "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, but also bind GTP and GDP and are involved in signal transduction.

[edit] Receptor-activated G proteins

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. When a ligand activates the G protein-coupled receptor, it induces a conformation change in the receptor (a change in shape) that allows the G protein to now bind to the receptor. The G protein then 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.

[edit] 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

[edit] 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.

[edit] Lipidation

Many G proteins are modified by having specific lipids attached to them, i.e. they are lipidated.

• Trimeric G proteins may be myristolated, palmitoylated, or prenylated.
• Small G proteins may be prenylated.

[edit] References

• Eric R. Kandel, James H. Schwartz, Thomas M. Jessell (2000). Principles of neural science. New York: McGraw-Hill. ISBN 0-8385-7701-6.
• 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.
• Gilman A (1987). "G proteins: transducers of receptor-generated signals.". Annu Rev Biochem 56: 615-49. PMID 3113327.

[edit] External links

• Animation of G protein