G Protein Signaling:
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins involved in transmitting chemical signals originating from 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. 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. 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.
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.
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. 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.
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
[expand title=”References for G protein signaling:”]
- 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.
- Reece J, C N (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.
- Neves SR, Ram PT, Iyengar R (May 2002). “G protein pathways”. Science 296 (5573): 1636–9. doi:10.1126/science.1071550. PMID 12040175.
- 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.
- Khafizov K, Lattanzi G, Carloni P (2009). “G protein inactive and active forms investigated by simulation methods”. PROTEINS : Structure, Function, and Bioinformatics75 (4): 919–30. doi:10.1002/prot.22303. PMID 19089952.
- 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.
- 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.PMID 17854654.