G protein
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{{Nofootnotes|date=February 2008}}
[[Image:1b9x opm.gif|thumb|250px|[[Phosducin]]- [[transducin]] beta-gamma complex. Beta and gamma subunits of G-protein are shown by blue and red, respectively.]]
[[Image:GDP chemical structure.png|thumb|180px|[[Guanosine diphosphate]]]][[Image:GTP chemical structure.png|thumb|180px|[[Guanosine triphosphate]]]]
'''G proteins,''' short for '''guanine nucleotide-binding proteins''', are a family of [[protein]]s involved in [[second messenger]] cascades.
G proteins are so called because they function as "molecular switches," alternating between an inactive [[guanosine diphosphate]] (GDP) and active [[guanosine triphosphate]] (GTP) bound state, ultimately going on to regulate downstream [[cell (biology)|cell]] processes.
G proteins were discovered when [[Alfred G. Gilman]] and [[Martin Rodbell]] tried to figure out how adrenaline stimulated cells. They found that when a hormone like adrenaline bound to a receptor, the receptor did not stimulate enzymes like [[adenylate cyclase]] directly. Instead, the receptor stimulated a G protein, which then stimulated the adenylate cyclase to produce a second messenger, [[cyclic AMP]].<ref>[http://nobelprize.org/nobel_prizes/medicine/laureates/1994/illpres/signal.html The Nobel Prize in Physiology or Medicine 1994], Illustrated Lecture.</ref> For this discovery they won the 1994 [[Nobel Prize in Physiology or Medicine]].<ref>[http://nobelprize.org/nobel_prizes/medicine/laureates/1994/press.html Press Release:] The Nobel Assembly at the Karolinska Institute has today 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</ref>
G proteins belong to the larger group of enzymes called [[GTPase]]s.
==Function==
G proteins are important [[signal transducing]] molecules in cells. In fact, diseases such as [[diabetes]] and certain forms of [[cancer]], among other pathologies, are thought to arise due to derangement of G protein signaling.
== Types of G protein signaling ==
G protein can refer to two distinct families of proteins. [[Heterotrimeric G protein]]s, sometimes referred to as the "large" G proteins that are activated by [[G protein-coupled receptor]]s and made up of alpha (α), beta (β), and gamma (γ) [[subunit]]s. There are also ''"small" G proteins'' (20-25kDa) that belong to the [[Ras]] superfamily of [[small GTPase]]s. 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===
{{Main|Heterotrimeric G proteins}}
Heterotrimeric G proteins share a common mode of action, i.e., activation in response to a conformation change in the [[G-protein-coupled receptor]], exchange of GTP for GDP and dissociation in order to activate further proteins in the [[signal transduction]] pathway. However, the specific mechanism differs between different types of G proteins.
====Common mechanism====
[[Image:GPCR-Zyklus.png|thumb|300px|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<sub>α</sub> and the tightly associated G<sub>βγ</sub> subunits. At the present time, four main families exist for G<sub>α</sub> subunits: G<sub>αs</sub>, G<sub>αi</sub>, G<sub>αq/11</sub>, and G<sub>α12/13</sub>. These groups differ primarily in effector recognition, but share a similar mechanism of activation.
=====Activation=====
When a [[ligand]] activates the [[G protein-coupled receptor]], it induces a conformation change in the receptor (a change in shape) that allows the receptor to function as a [[guanine nucleotide exchange factor]] ([[GEF]]) that exchanges GTP in place of GDP on the G<sub>α</sub> subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the G<sub>α</sub> subunit, bound to GTP, from the G<sub>βγ</sub> dimer and the receptor. However, models that suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted. Both G<sub>α</sub>-GTP and G<sub>βγ</sub> 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<sub>α</sub> subunit will eventually [[Hydrolysis|hydrolyze]] the attached GTP to GDP by its inherent [[enzyme|enzymatic]] activity, allowing it to re-associate with G<sub>βγ</sub> and starting a new cycle. There do exist groups of proteins called RBMs that act as [[GTPase-activating proteins]] (GAPs), which are specific for G<sub>α</sub> subunits, which act to accelerate hydrolysis 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 G<sub>α</sub> subunit.
====Specific mechanisms====
*'''[[Gαs|G<sub>αs</sub>]]''' stimulates the production of [[cyclic AMP|cAMP]] from [[adenosine triphosphate|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 of downstream targets.
*'''[[Gαi|G<sub>αi</sub>]]''' inhibits the production of cAMP from ATP.
*'''[[Gαq|G<sub>αq/11</sub>]]''' stimulates membrane-bound [[phospholipase C]] beta, which then cleaves PIP<sub>2</sub> (a minor membrane phosphoinositol) into two second messengers, [[IP3]] and [[diglyceride|diacylglycerol]] (DAG).
*'''[[G12/G13 alpha subunits|G<sub>α12/13</sub>]]''' are involved in Rho family GTPase signaling (through RhoGEF superfamily) and control cell cytoskeleton remodeling, thus regulating cell migration.
*'''[[G beta gamma subunits|G<sub>βγ</sub>]]''' sometimes also have active functions, e.g., coupling to [[L-type calcium channel]]s.
===Small GTPases===
{{Main|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) [[protein]]s that bind to guanosine triphosphate ([[Guanosine triphosphate|GTP]]). This family of proteins is [[Homology_(biology)|homologous]] to [[Ras_%28protein%29|Ras GTPases]] and is also called the Ras superfamily [[GTPase]]s.
== Lipidation ==
In order to associate with the inner leaflet of the plasma membrane, many G proteins are covalently modified with lipid extensions, i.e., they are lipidated.
* Heterotrimeric G protein subunits may be [[myristolated]], [[palmitoylated]], or [[prenylated]].
* Small G proteins may be prenylated.
== References ==
<references/>
* {{cite book | author=Eric R. Kandel, James H. Schwartz, Thomas M. Jessell | title=Principles of Neural Science | publisher=McGraw-Hill | location=New York | year=2000 | id=ISBN 0-8385-7701-6}}
* {{cite book | author = Lodish H, Berk A, Zipursky LS, Matsudaira P, Baltimore D, Darnell J | title = Molecular Cell Biology | publisher = Scientific American Books | location = New York | edition = 4<sup>th</sup> ed. | year = 1999 | pages = | isbn = 0-7167-3136-3 | oclc = | doi = }}
* {{cite book | author = Voet, Judith G.; Voet, Donald | title = Biochemistry | publisher = J. Wiley & Sons | location = New York | edition = 2<sup>nd</sup> ed.| year = 1995 | pages = | isbn = 0-471-58651-X | oclc = | doi = }}
* {{cite journal | author = Gilman AG | title = G proteins: transducers of receptor-generated signals | journal = Annu. Rev. Biochem. | volume = 56 | issue = | pages = 615–49 | year = 1987 | pmid = 3113327 | doi = 10.1146/annurev.bi.56.070187.003151 | issn = }}
* {{cite journal | author = Neves SR, Ram PT, Iyengar R | title = G protein pathways | journal = Science | volume = 296 | issue = 5573 | pages = 1636–9 | year = 2002 | pmid = 12040175 | doi = 10.1126/science.1071550 | issn = }}
==External links==
* [http://www.mmmp.org/MMMP/public/biomap/listBiomap.mmmp G proteins and the RAS superfamily]
{{Carrier proteins}}
{{GTPases}}
[[Category:G proteins|*]]
[[Category:Membrane biology]]
[[Category:Peripheral membrane proteins]]
[[Category:Cell signaling]]
[[Category:Signal transduction]]
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