G proteins, also known asguanine nucleotide-binding proteins, are afamily of proteins that act asmolecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside acell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyzeguanosine triphosphate (GTP) toguanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group ofenzymes calledGTPases.
There are two classes of G proteins. The first function asmonomericsmall GTPases (small G-proteins), while the second function asheterotrimeric G proteincomplexes. The latter class of complexes is made up ofalpha (Gα),beta (Gβ) andgamma (Gγ)subunits.[1] In addition, the beta and gamma subunits can form a stabledimeric complex referred to as thebeta-gamma complex.[2]
Heterotrimeric G proteins located within the cell are activated byG protein-coupled receptors (GPCRs) that span thecell membrane.[3]Signaling molecules bind to a domain of the GPCR located outside the cell, and an intracellular GPCR domain then in turn activates a particular G protein. Some active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur.[4][5][6] The G protein triggers acascade of further signaling events that finally results in a change in cell function. G protein-coupled receptors and G proteins working together transmit signals from manyhormones,neurotransmitters, and other signaling factors.[7] G proteins regulate metabolicenzymes,ion channels,transporter proteins, and other parts of the cell machinery, controllingtranscription,motility,contractility, andsecretion, which in turn regulate diverse systemic functions such asembryonic development, learning and memory, andhomeostasis.[8]
G proteins were discovered in 1980 whenAlfred G. Gilman andMartin Rodbell investigated stimulation of cells byadrenaline. They found that when adrenaline binds to a receptor, the receptor does not stimulate enzymes (inside the cell) directly. Instead, the receptor stimulates a G protein, which then stimulates an enzyme. An example isadenylate cyclase, which produces thesecond messengercyclic AMP.[9] For this discovery, they won the 1994Nobel Prize in Physiology or Medicine.[10]
Nobel prizes have been awarded for many aspects of signaling by G proteins and GPCRs. These includereceptor antagonists,neurotransmitters, neurotransmitterreuptake,G protein-coupled receptors, G proteins,second messengers, the enzymes that trigger proteinphosphorylation in response tocAMP, and consequent metabolic processes such asglycogenolysis.
Prominent examples include (in chronological order of awarding):
G proteins are importantsignal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such asdiabetes, blindness, allergies, depression, cardiovascular defects, and certain forms ofcancer. It is estimated that about 30% of the modern drugs' cellular targets are GPCRs."[15] The human genome encodes roughly 800[16]G protein-coupled receptors, which detect photons of light, hormones, growth factors, drugs, and other endogenousligands. Approximately 150 of the GPCRs found in the human genome still have unknown functions.
Whereas G proteins are activated byG protein-coupled receptors, they are inactivated byRGS proteins (for "Regulator of G protein signalling"). Receptors stimulate GTP binding (turning the G protein on). RGS proteins stimulate GTP hydrolysis (creating GDP, thus turning the G protein off).
All eukaryotes use G proteins for signaling and have evolved a large diversity of G proteins. For instance, humans encode 18 different Gα proteins, 5 Gβ proteins, and 12 Gγ proteins.[17]
G protein can refer to two distinct families of proteins.Heterotrimeric G proteins, sometimes referred to as the "large" G proteins, are activated byG protein-coupled receptors and are made up of alpha (α), beta (β), and gamma (γ)subunits."Small" G proteins (20-25kDa) belong to theRas superfamily ofsmall GTPases. These proteins arehomologous to the alpha (α) subunit found in heterotrimers, but are in fact monomeric, consisting of only a single unit. However, like their larger relatives, they also bind GTP and GDP and are involved insignal transduction.
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to aconformational change in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particularsignal transduction pathway.[18] The specific mechanisms, however, differ between protein types.
Receptor-activated G proteins are bound to the inner surface of thecell membrane. They consist of the Gα and the tightly associated Gβγ subunits. There are four main families of Gα subunits: Gαs (G stimulatory), Gαi (G inhibitory), Gαq/11, and Gα12/13.[20][21] They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation.
When aligand activates theG protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as aguanine nucleotide exchange factor (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the Gα subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the Gα subunit (which is bound to GTP) from the Gβγ dimer and the receptor as a whole. However, models which suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted.[4][22][23] Both Gα-GTP and Gβγ can then activate differentsignaling cascades (orsecond messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.[24]
The Gα subunit will eventuallyhydrolyze the attached GTP to GDP by its inherentenzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. A group of proteins calledRegulator of G protein signalling (RGSs), act asGTPase-activating proteins (GAPs), are specific for Gα subunits. These proteins accelerate the hydrolysis of GTP to GDP, thus terminating the transduced signal. In some cases, the effectoritself may possess intrinsic GAP activity, which then can help deactivate the pathway. This is true in the case ofphospholipase C-beta, which possesses GAP activity within itsC-terminal region. This is an alternate form of regulation for the Gα subunit. Such Gα GAPs do not have catalytic residues (specific amino acid sequences) to activate the Gα protein. They work instead by lowering the requiredactivation energy for the reaction to take place.[25]
Gαs activates thecAMP-dependent pathway by stimulating the production ofcyclic AMP (cAMP) fromATP. This is accomplished by direct stimulation of the membrane-associated enzymeadenylate cyclase. cAMP can then act as a second messenger that goes on to interact with and activateprotein kinase A (PKA). PKA can phosphorylate a myriad downstream targets.
ThecAMP-dependent pathway is used as a signal transduction pathway for many hormones including:
Gαi inhibits the production of cAMP from ATP.e.g. somatostatin, prostaglandins
Gαq/11 stimulates the membrane-boundphospholipase C beta, which then cleavesphosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers,inositol trisphosphate (IP3) anddiacylglycerol (DAG). IP3 induces calcium release from theendoplasmic reticulum. DAG activatesprotein kinase C.The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
Small GTPases, also known as small G-proteins, bind GTP and GDP likewise, and are involved insignal 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 theRas GTPases and is also called the Ras superfamilyGTPases.
In order to associate with the inner leaflet of the plasma membrane, many G proteins and small GTPases are lipidated[citation needed], that is, covalently modified with lipid extensions. They may bemyristoylated,palmitoylated orprenylated.
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