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| '''GTPases''' (singular GTPase) are a large family of [[hydrolase]] [[enzyme]]s that can bind and [[hydrolysis|hydrolyze]] [[Guanosine triphosphate|guanosine triphosphate (GTP)]].<ref name="pmid16314935">{{cite journal | author = Scheffzek K, Ahmadian MR | title = GTPase activating proteins: structural and functional insights 18 years after discovery | journal = Cellular and Molecular Life Sciences : CMLS | volume = 62 | issue = 24 | pages = 3014–38 |date=December 2005 | pmid = 16314935 | doi = 10.1007/s00018-005-5136-x }}</ref> The GTP binding and hydrolysis takes place in the highly [[Conserved sequence|conserved]] ''G [[domain (protein)|domain]]'' common to all '''GTPases'''.
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| ==Functions==
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| GTPases play an important role in:
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| * [[Signal transduction]] at the intracellular domain of [[G protein-coupled receptor|transmembrane receptor]]s, including recognition of taste, smell and light.
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| * [[Protein biosynthesis]] (aka [[translation (biology)|translation]]) at the [[ribosome]].
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| * Control and [[cellular differentiation|differentiation]] during [[cell division]].
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| * [[Protein targeting#Protein translocation|Translocation]] of [[protein]]s through [[cell membrane|membrane]]s.
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| * Transport of [[vesicle (biology)|vesicle]]s within the [[cell (biology)|cell]]. (GTPases control assembly of vesicle coats).
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| == Mechanism ==
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| The hydrolysis of the γ [[phosphate]] of GTP into [[guanosine diphosphate]] (GDP) and P<sub>i</sub>, [[inorganic phosphate]], occurs by the S<sub>N</sub>2 mechanism (see [[nucleophilic substitution]]) via a ''pentavalent intermediate state'' and is dependent on the [[magnesium]] [[ion]] Mg<sup>2+</sup>.
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| ==Major motifs==
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| In most GTPases, the specificity for the base [[guanine]] is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. <ref>{{cite journal |author=Leipe D.D., Wolf Y.I., Koonin E.V., and Aravind, L. |title=Classification and evolution of P-loop GTPases and related ATPases |journal=J. Mol. Biol. |volume=317 |issue=1 |pages=41–72 |year=2002 |doi=10.1006/jmbi.2001.5378 |pmid=11916378}}</ref>
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| ==Regulatory GTPases==
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| Regulatory GTPases, also called the [[GTPase superfamily]], are GTPases used for regulation of other [[biochemistry|biochemical]] processes. Most prominent among the regulatory GTPases are the G proteins.
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| ===GTP switch===
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| All regulatory GTPases have a common mechanism that enables them to switch a [[signal transduction]] chain on and off. Toggling the switch is performed by the unidirectional change of the GTPase from the ''active, [[Guanosine triphosphate|GTP]]-bound form'' to the ''inactive, [[guanosine diphosphate|GDP]]-bound form'' by [[hydrolysis]] of the GTP through intrinsic GTPase-activity, effectively switching the GTPase ''off''. This reaction is initiated by [[GTPase-activating protein]]s (GAPs), coming from another signal transduction pathway. It can be reversed (switching the GTPase ''on'' again) by [[Guanine nucleotide exchange factor]]s (GEFs), which cause the GDP to dissociate from the GTPase, leading to its association with a new GTP. This closes the cycle to the active state of the GTPase; the irreversible hydrolysis of the GTP to GDP forces the cycle to run only in one direction. Only the active state of the GTPase can transduce a signal to a reaction chain.
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| ===Switch regulation===
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| The efficiency of the signal transduction via a GTPase depends on the ratio of active to inactive GTPase. That
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| equals:
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| <!--
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| :GTPase*GTP k<sub>diss.GDP</sub>
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| :<sup>__________</sup> = <sup>_________</sup>
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| :GTPase*GDP k<sub>cat.GTP</sub>
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| --> | |
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| :<math>
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| \frac {\mbox{GTPase}*\mbox{GTP}} {\mbox{GTPase}*\mbox{GDP}} =
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| \frac {k_\mbox{diss.GDP}} {k_\mbox{cat.GTP}}
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| </math>
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| with ''k<sub>diss.GDP</sub>'' being the dissociation constant of GDP, and ''k<sub>cat.GTP</sub>'' the hydrolysis constant of GTP for the specific GTPase. Both constants can be modified by special regulatory proteins.<br>
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| The amount of active GTPase can be changed in several ways :
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| # Acceleration of GDP dissociation by GEFs speeds up the building of active GTPase.
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| # Inhibition of GDP dissociation by [[Guanine nucleotide dissociation inhibitors]] (GDIs) slows down the building of active GTPase.
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| # Acceleration of GTP hydrolysis by GAPs reduces the amount of active GTPase.
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| # ''GTP analogues'' like ''γ-S-GTP'', ''β,γ-methylene-GTP'', and ''β,γ-imino-GTP'' that cannot be hydrolyzed fixate the GTPase in its active state.
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| ==Heterotrimeric G proteins==
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| These G proteins are made from three subunits, with the G domain located on the largest one (the ''α unit''); together with the two smaller subunits (''β'' and ''γ units''), they form a tightly associated protein complex. α and γ unit are associated with the membrane by [[lipid anchor]]s. Heterotrimeric G proteins act as the specific reaction partners of [[G protein-coupled receptor]]s. The GTPase is normally inactive. Upon receptor activation, the intracellular receptor domain activates the GTPase, which in turn activates other molecules of the signal transduction chain, either via the α unit or the βγ complex. Among the target molecules of the active GTPase are [[adenylate cyclase]] and [[ion channel]]s. The heterotrimeric G proteins can be classified by [[sequence homology]] of the α unit into four families:
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| # ''G<sub>s</sub> family.'' These G proteins are used in the signal transduction of taste and smell. They always use the activation of [[adenylate cyclase]] as the next step in the signal chain. The <sub>s</sub> stands for stimulation. Their function is permanently activated by the [[cholera toxin]], which is the cause of the fatal effects of infection with ''[[Vibrio cholerae]]''.
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| # ''G<sub>i</sub> family.'' The ''i'' stands for ''inhibition'' of the [[adenylate cyclase]]; another effector molecule for this protein family is ''[[phospholipase]] C''. Also, G<sub>t</sub> and G<sub>g</sub> proteins are summarized under this label due to sequence homologies. G<sub>t</sub> proteins, aka [[transducin]], is used in the light recognition pathway in retina cells. G<sub>g</sub> protein occurs in the taste recognition for ''bitter''. Most G<sub>i</sub> protein family members can be inhibited by the [[pertussis toxin]] of ''[[Bordetella pertussis]]''.
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| # ''G<sub>q</sub> family.'' These proteins usually have [[phospholipase]] C as effector protein.
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| # ''G<sub>12</sub> family.'' These G proteins can be activated by [[thromboxan receptor]]s and [[thrombin receptor]]s. Their effector proteins are unknown.
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| By combination of different α, β and γ subunits, a great variety (>1000) G proteins can be produced.
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| GDP is not needed for GTP.
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| ===Activation cycle of heterotrimeric G proteins===
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| In the basic state, the G<sub>α</sub>-GDP-G<sub>βγ</sub> complex and the receptor that can activate it are separately associated with the membrane. On receptor activation, the receptor becomes highly [[electron affinity|affine]] for the G protein - GDP complex. On binding with the complex, GDP dissociates from the complex; the receptor works as a GEF - GDP-GTP Exchange Factor; the ''free'' complex has a high affinity for GTP. Upon GTP binding, both G<sub>α</sub>-GTP and G<sub>βγ</sub> separate from both the receptor and from each other. Depending on the lifetime of the active state of the receptor, it can activate more G proteins this way.<br>
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| Both G<sub>α</sub>-GTP and G<sub>βγ</sub> can now activate separate and/or the same effector molecules, thus sending the signal further down the signal reaction chain. Once the intrinsic GTPase activity of the α unit has hydrolyzed the GTP to GDP, and then the two parts associate to the original, inactive state. The speed of the hydrolysis reaction works as an internal clock for the length of the signal.
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| ==The Ras GTPase superfamily==
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| These are small monomeric proteins homologous to [[Ras (protein)|Ras]]. They are also called [[small GTPase]]s. Small GTPases have a molecular weight of about 21 kilodaltons and generally serve as molecular switches for a variety of cellular signaling events. According to their primary amino acid sequences and biochemical properties, the Ras superfamily is further divided into five subfamilies: [[Ras (protein)|Ras]], [[Rho family of GTPases|Rho]], [[Rab (G-protein)|Rab]], [[ADP ribosylation factor|Arf]] and [[Ran protein|Ran]]. The [[Rho family of GTPases|Rho]] subfamily is further divided into RHOA, RAC1, and CDC42.<ref>{{cite journal |author=Hippenstiel S, Schmeck B, N'Guessan PD, ''et al.'' |title=Rho protein inactivation induced apoptosis of cultured human endothelial cells |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=283 |issue=4 |pages=L830–8 |date=October 2002 |pmid=12225960 |doi=10.1152/ajplung.00467.2001 |url=http://ajplung.physiology.org/cgi/pmidlookup?view=long&pmid=12225960}}</ref>
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| ==[[Translation (biology)|Translation]] factor family==
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| These GTPases play an important role in [[initiation]], [[Eukaryotic translation#Elongation|elongation]] and termination of [[protein biosynthesis]].
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| ==[[Protein translocation|Translocation]] factors==
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| See [[signal recognition particle]] (SRP).
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| ==[[Large GTPase]]s==
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| See [[dynamin]] as a prototype for large GTPases.
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| ==See also==
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| * [[G protein-coupled receptors]]
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| * [[Rho-kinase]]
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| == References ==
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| {{reflist}}
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| ==External links==
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| * [http://www.mechanobio.info/Home/glossary-of-terms/mechano-glossary--p/Rho-family-of-GTPases#cdc42 MBInfo - RhoGTPases]
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| * {{MeshName|GTPase}}
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| * [http://www.genecards.org/cgi-bin/carddisp.pl?gene=NF1 Neurofibromin 1] from [[GeneCards]]
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| {{Acid anhydride hydrolases}}
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| [[Category:Signal transduction]]
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| [[Category:EC 3.6.5]]
| |
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