GTP-binding protein

• GTP結合タンパク質、GTP結合蛋白質

関

G-protein

WordNet

1. executed with proper legal authority; "a binding contract"
2. the protective covering on the front, back, and spine of a book; "the book had a leather binding" (同)book binding, cover, back
3. strip sewn over or along an edge for reinforcement or decoration
4. the capacity to attract and hold something
5. any of a large group of nitrogenous organic compounds that are essential constituents of living cells; consist of polymers of amino acids; essential in the diet of animals for growth and for repair of tissues; can be obtained from meat and eggs and milk and legumes; "a diet high in protein"
6. the 7th letter of the Roman alphabet (同)g

PrepTutorEJDIC

1. 義務的な,拘束力ある / 〈U〉しばること;〈C〉しばる物 / 〈C〉製本,装丁 / 〈U〉縁(‘ふち')取り材料
2. 蛋白(たんばく)質

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/03 15:56:58」(JST)

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Not to be confused with Protein G.

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, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine 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 of enzymes called GTPases.

There are two classes of G proteins. The first function as monomeric small GTPases, while the second form and function as heterotrimeric G protein complexes. The latter class of complexes is made up of alpha (α), beta (β) and gamma (γ) subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex.

G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. 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 inactive-state GPCRs have also been shown to be "pre-coupled" with G proteins. The G protein activates a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptor and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate diverse systemic functions such as embryonic development, learning and memory, and homeostasis.

History

G proteins were discovered when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline. 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 is adenylate cyclase, which produces the second messenger cyclic AMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.

Nobel prizes have been awarded for many aspects of signaling by G proteins and GCPRs. These include receptor antagonists, neurotransmitters, neurotransmitter reuptake, G protein-coupled receptors, G proteins, second messengers, the enzymes that trigger protein phosphorylation in response to cAMP, and consequent metabolic processes such as glycogenolysis.

Prominent examples include (in chronological order of awarding):

• The 1947 Nobel Prize in Physiology or Medicine to Carl Cori, Gerty Cori and Bernardo Houssay, for their discovery of how glycogen is broken down to glucose and resynthesized in the body, for use as a store and source of energy. Glycogenolysis is stimulated by numerous hormones and neurotransmitters including adrenaline.

• The 1970 Nobel Prize in Physiology or Medicine to Julius Axelrod, Bernard Katz and Ulf von Euler for their work on the release and reuptake of neurotransmitters.

• The 1971 Nobel Prize in Physiology or Medicine to Earl Sutherland for discovering the key role of adenylate cyclase, which produces the second messenger cyclic AMP.

• The 1988 Nobel Prize in Physiology or Medicine to George H. Hitchings, Sir James Black and Gertrude Elion "for their discoveries of important principles for drug treatment" targeting GPCRs.

• The 1992 Nobel Prize in Physiology or Medicine to Edwin G. Krebs and Edmond H. Fischer for describing how reversible phosphorylation works as a switch to activate proteins, and to regulate various cellular processes including glycogenolysis.

• The 1994 Nobel Prize in Physiology or Medicine to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells".

• The 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson and Paul Greengard, for research on neurotransmitters such as dopamine, which act via GPCRs.

• The 2004 Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled olfactory receptors.

• The 2012 Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz for their work on GPCR function.

Function

G proteins are important signal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that about 30% of the modern drugs' cellular targets are GPCRs." The human genome encodes roughly 800 G protein-coupled receptors, which detect photons of light, hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have still-unknown functions.

Whereas G proteins are activated by G protein-coupled receptors, they are inactivated by RGS 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).

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, are activated by G protein-coupled receptors and are made up of alpha (α), beta (β), and gamma (γ) subunits. "Small" G proteins (20-25kDa) belong to the Ras superfamily of small GTPases. These proteins are homologous 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 in signal transduction.

Heterotrimeric G proteins

Main article: Heterotrimeric G proteins

Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformational change in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particular signal transduction pathway. The specific mechanisms, however, differ between protein types.

Common mechanism

Activation cycle of a G-protein (purple) by a G-protein-coupled receptor (light blue) receiving a ligand (red).

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 many classes of G_α subunits: G_sα (G stimulatory), G_iα (G inhibitory), G_oα (G other), G_q/11α, and G_12/13α are some examples. They behave differently in the recognition of the effector molecule, 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 - thus turning the GPCR "on". The GTP (or GDP) is bound to the G_α subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the G_α subunit (which is bound to GTP) from the G_βγ 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. 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 Regulator of G protein signalling (RGSs), act as GTPase-activating proteins (GAPs), are specific for G_α subunits. These proteins accelerate the hydrolysis of GTP to GDP, thus terminating the transduced signal. In some cases, the effector itself may possess intrinsic GAP activity, which then can help 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. However, it should be noted that such G_α GAPs do not have catalytic residues (specific amino acid sequences) to activate the G_α protein. They work instead by lowering the required activation energy for the reaction to take place.

Specific mechanisms

G_αs

G_αs activates the cAMP-dependent pathway by stimulating the production of cyclic AMP (cAMP) from ATP. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclase. cAMP can then act as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can phosphorylate a myriad downstream targets.

The cAMP Dependent Pathway is used as a signal transduction pathway for many hormones including:

• ADH - Promotes water retention by the kidneys (created by the V2 Cells of Posterior Pituitary)
• GHRH - Stimulates the synthesis and release of GH (Somatotroph Cells of Anterior Pituitary)
• GHIH - Inhibits the synthesis and release of GH (Somatotroph Cells of Anterior Pituitary)
• CRH - Stimulates the synthesis and release of ACTH (Anterior Pituitary)
• ACTH - Stimulates the synthesis and release of Cortisol (zona fasiculata of adrenal cortex in kidneys)
• TSH - Stimulates the synthesis and release of a majority of T4 (Thyroid Gland)
• LH - Stimulates follicular maturation and ovulation in women; or testosterone production and spermatogenesis in men
• FSH - Stimulates follicular development in women; or spermatogenesis in men
• PTH - Increases blood calcium levels. This is accomplished via the Parathyroid hormone 1 receptor (PTH1) in the kidneys and bones, or via the Parathyroid hormone 2 receptor (PTH2) in the central nervous system and brain, as well as the bones and kidneys.
• Calcitonin - Decreases blood calcium levels (via the calcitonin receptor in the intestines, bones, kidneys, and brain)
• Glucagon - Stimulates glycogen breakdown in the liver
• hCG - Promotes cellular differentiation, and is potentially involved in apoptosis.
• Epinephrine - released by the adrenal medulla during the fasting state, when body is under metabolic duress. It stimulates glycogenolysis, in addition to the actions of glucagon.

G_αi

G_αi inhibits the production of cAMP from ATP.

Insulin works through G_i (inhibitory) second messenger proteins.

G_αq/11

G_αq/11 stimulates the membrane-bound phospholipase C beta, which then cleaves PIP₂ (a minor membrane phosphoinositol) into two second messengers, IP3 and diacylglycerol (DAG). The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:

• ADH (Vasopressin/AVP) - Induces the synthesis and release of glucocorticoids (Zona fasciculata of adrenal cortex in kidney); Induces vasoconstriction (V1 Cells of Posterior pituitary)
• TRH - Induces the synthesis and release of TSH (Anterior pituitary)
• TSH - Induces the synthesis and release of a small amount of T4 (Thyroid Gland)
• Angiotensin II - Induces Aldosterone synthesis and release (zona glomerulosa of adrenal cortex in kidney)
• GnRH - Induces the synthesis and release of FSH and LH (Anterior Pituitary)

G_α12/13

• G_α12/13 are involved in Rho family GTPase signaling (see Rho family of GTPases). This is through the RhoGEF superfamily involving the RhoGEF domain of the proteins' structures). These are involved in control of cell cytoskeleton remodeling, and thus in regulating cell migration.

G_β

• The G_βγ complexes sometimes also have active functions. Examples include coupling to and activating G protein-coupled inwardly-rectifying potassium channels.

Small GTPases

Main article: 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 the 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

External links

• GTP-Binding Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)

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English Journal

• Rab3A, a possible marker of cortical granules, participates in cortical granule exocytosis in mouse eggs.

• Bello OD1, Cappa AI1, de Paola M1, Zanetti MN1, Fukuda M2, Fissore RA3, Mayorga LS1, Michaut MA4.
• Experimental cell research.Exp Cell Res.2016 Sep 10;347(1):42-51. doi: 10.1016/j.yexcr.2016.07.005. Epub 2016 Jul 14.
• Fusion of cortical granules with the oocyte plasma membrane is the most significant event to prevent polyspermy. This particular exocytosis, also known as cortical reaction, is regulated by calcium and its molecular mechanism is still not known. Rab3A, a member of the small GTP-binding protein super
• PMID 27423421

• Dimethyloxalylglycine Promotes Bone Marrow Mesenchymal Stem Cell Osteogenesis via Rho/ROCK Signaling.

• Zhang L1, Jiang G, Zhao X, Gong Y.
• Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology.Cell Physiol Biochem.2016 Sep 8;39(4):1391-1403. [Epub ahead of print]
• BACKGROUND/AIMS: We investigated the role of dimethyloxalylglycine (DMOG) in bone marrow mesenchymal stem cell (BMSC) osteogenesis mediated by RhoA/ROCK.METHODS: BMSCs were cultured with and without DMOG and/or Y-27632 (ROCK1 inhibitor). Cell proliferation, alkaline phosphatase (ALP) levels, and cal
• PMID 27606625

• The Structural Basis for Cdc42-Induced Dimerization of IQGAPs.

• LeCour L Jr1, Boyapati VK1, Liu J1, Li Z2, Sacks DB2, Worthylake DK3.
• Structure (London, England : 1993).Structure.2016 Sep 6;24(9):1499-508. doi: 10.1016/j.str.2016.06.016. Epub 2016 Aug 11.
• In signaling, Rho-family GTPases bind effector proteins and alter their behavior. Here we present the crystal structure of Cdc42·GTP bound to the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP2. Four molecules of Cdc42 are bound to two GRD molecules, which bind each other in a parall
• PMID 27524202

Japanese Journal

• Rho Kinases and Cardiac Remodeling

• Circulation Journal 80(7), 1491-1498, 2016
• NAID 130005158914

• Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]

• Endocrine Journal advpub(0), 2016
• NAID 130005157162

• Rho Kinases and Cardiac Remodeling

• Circulation Journal advpub(0), 2016
• NAID 130005155421

Related Links

• GTP Binding Proteins - UW Courses Web Server

Trimeric G Proteins The trimeric G-proteins (GTP binding proteins) play a pivotal role in the signal transduction pathways for numerous hormones and neurotransmitters. The three subunits of the protein are labelled alpha, beta, and gamma

• GTP binding protein - definition of GTP binding protein by ...

Further, recent studies indicate that an RNA polymerase-associated small regulatory protein, called DksA, and a conserved essential GTP binding protein CgtA are also involved in regulation of stringent response by modulating the ...

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★リンクテーブル★

リンク元	「G-protein」「Gタンパク質」
拡張検索	「G12-G13 GTP-binding protein alpha subunit」「Gi2 GTP-binding protein alpha subunit」「Rab1 GTP-binding protein」「Rab4 GTP-binding protein」
関連記事	「binding」「GTP」「binding protein」「G」

「G-protein」

　　[★] Gタンパク質、G蛋白質、Gタンパク、G蛋白、GTP結合タンパク質、GTP結合調節タンパク質

関

GTP-binding protein、GTP-binding regulatory protein

同

guanine nucleotide-binding protein

「Gタンパク質」

　　[★]

英

G-protein, G protein

同

G蛋白質、G蛋白、Gタンパク、GTP-結合タンパク GTP-結合タンパク質 GTP-binding protein

「G12-G13 GTP-binding protein alpha subunit」

　　[★]

GTP結合タンパク質G12/13αサブユニット

関

G12 protein、G13 protein

「Gi2 GTP-binding protein alpha subunit」

　　[★]

GTP結合タンパク質Gi2αサブユニット

「Rab1 GTP-binding protein」

　　[★]

GTP結合タンパク質Rab1

「Rab4 GTP-binding protein」

　　[★]

GTP結合タンパク質Rab4

「binding」

　　[★]

• n.

• 結合、バインディング

• adj.

• 結合性の

関

affinity、associate、bind、bond、bonding、combine、conjoin、conjugate、conjugation、conjunction、connect、connection、connective、connectivity、couple、dock、engage、engagement、join、ligate、linkage、symphysial、symphysic、union

　 　 　 　 　

「GTP」

　　[★]

• グアノシン三リン酸 guanosine triphosphate
• グルタミルトランスペプチダーゼ　→　γ-グルタミルトランスペプチダーゼ

「binding protein」

　　[★]

• 結合タンパク質、結合タンパク、結合蛋白質、結合蛋白

関

BP、carrier protein、transport protein

「G」

　　[★]

• グアニン guanine
• グアノシン guanosine
• グリシン glycine