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.

G proteins, also known as guanosine nucleotide-binding proteins, are a family of proteins involved in transmitting signals from a variety of different stimuli outside a cell into the inside of the cell. G proteins function as molecular switches. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they bind GTP, they are 'on', and, when they bind 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 are made up of alpha (α), beta (β) and gamma (γ) subunits.[1] 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. An intracellular GPCR domain in turn activates a G protein. 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.[2] 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.[3]

History[edit]

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 directly. Instead, the receptor stimulates a G protein, which stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP.[4] For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.[5]

Function[edit]

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." [6]

The human genome encodes roughly 800 [7] G protein-coupled receptors, which detect photons (light), hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.

Types of G protein signaling[edit]

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[edit]

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[edit]

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 Gα and the tightly associated Gβγ subunits. There are many classes of Gα subunits: Gsα (G stimulatory), Giα (G inhibitory), Goα (G other), Gq/11α, and G12/13α are some examples. They behave differently in the recognition of the effector, but share a similar mechanism of activation.

Activation[edit]

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 GTP in place of GDP on the Gα subunit in the traditional view of heterotrimeric protein activation. This exchange triggers the dissociation of the Gα subunit, bound to GTP, from the Gβγ dimer and the receptor. However, models that suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted.[8][9] Both Gα-GTP and Gβγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.[10]

Termination[edit]

The Gα subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. A group of proteins called Regulator of G protein signalling (RGSs), act as GTPase-activating proteins (GAPs), specific for Gα subunits. These proteins act to accelerate hydrolysis of GTP to GDP 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 Gα subunit. However, it should be noted that the Gα GAPs do not have catalytic residues to activate the Gα protein. It works instead by lowering the required activation energy for the reaction to take place.[11]

Specific mechanisms[edit]

Gαs[edit]

Gαs 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 downstream targets.

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

Gαi[edit]

Gαi inhibits the production of cAMP from ATP.

Insulin works through Gi (inhibitory) second messenger proteins.

Gαq/11[edit]

Gαq/11 stimulates 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:

Gα12/13[edit]
Gβ[edit]

Small GTPases[edit]

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[edit]

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[edit]

  1. ^ Hurowitz EH, Melnyk JM, Chen YJ, Kouros-Mehr H, Simon MI, Shizuya H (2000). "Genomic characterization of the human heterotrimeric G protein alpha, beta, and gamma subunit genes". DNA Res 7 (2): 111–20. doi:10.1093/dnares/7.2.111. PMID 10819326. 
  2. ^ Reece J, C N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5. 
  3. ^ Neves SR, Ram PT, Iyengar R (May 2002). "G protein pathways". Science 296 (5573): 1636–9. doi:10.1126/science.1071550. PMID 12040175. 
  4. ^ The Nobel Prize in Physiology or Medicine 1994, Illustrated Lecture.
  5. ^ Press Release: The Nobel Assembly at the Karolinska Institute 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
  6. ^ Bosch DE, Siderovski DP (2013). "G protein signaling in the parasite Entamoeba histolytica". Experimental & Molecular Medicine 10 (1038): 1–12. 
  7. ^ Baltoumas FA, Theodoropoulou MC, Hamodrakes SJ (2013). "Interactions of the alpha subunits of heterotrimeric G-proteins with GPCRs, effectors and RGS proteins: A critical review and analysis of interacting surfaces, conformational shifts, structural diversity and electrostatic potentials". Journal of Structural Biology 10 (1016). 
  8. ^ Digby GJ, Lober RM, Sethi PR, Lambert NA. (2006). "Some G protein heterotrimers physically dissociate in living cells". Proc Natl Acad Sci USA 103 (47): 17789–94. doi:10.1073/pnas.0607116103. PMC 1693825. PMID 17095603. 
  9. ^ Khafizov K, Lattanzi G, Carloni P (2009). "G protein inactive and active forms investigated by simulation methods". Proteins : Structure, Function, and Bioinformatics 75 (4): 919–30. doi:10.1002/prot.22303. PMID 19089952. 
  10. ^ Yuen JW, Poon LS, Chan AS, Yu FW, Lo RK, Wong YH (June 2010). "Activation of STAT3 by specific Galpha subunits and multiple Gbetagamma dimers". Int. J. Biochem. Cell Biol. 42 (6): 1052–9. doi:10.1016/j.biocel.2010.03.017. PMID 20348012. 
  11. ^ Sprang, SR; Chen, Z; Du, X (2007). "Structural basis of effector regulation and signal termination in heterotrimeric Galpha proteins.". Advances in protein chemistry 74: 1–65. doi:10.1016/S0065-3233(07)74001-9. PMID 17854654. 

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