Editing GTPase (section)

=====Heterotrimeric G proteins=====
{{main|Heterotrimeric G protein}}
[[Heterotrimeric G protein]] complexes are composed of three distinct protein subunits named ''[[G alpha subunit|alpha]]'' (α), ''beta'' (β) and ''gamma'' (γ) [[protein subunit|subunit]]s.<ref name="pmid10819326">{{cite journal | vauthors = Hurowitz EH, Melnyk JM, Chen YJ, Kouros-Mehr H, Simon MI, Shizuya H | title = Genomic characterization of the human heterotrimeric G protein alpha, beta, and gamma subunit genes | journal = DNA Research | volume = 7 | issue = 2 | pages = 111–20 | date = April 2000 | pmid =10819326 | doi = 10.1093/dnares/7.2.111 | doi-access = free }}</ref> The alpha subunits contain the GTP binding/GTPase domain flanked by long regulatory regions, while the beta and gamma subunits form a stable dimeric complex referred to as the [[G beta-gamma complex|beta-gamma complex]].<ref name="pmid9131251">{{cite journal |vauthors=Clapham DE, Neer EJ |title=G protein beta gamma subunits |journal=Annual Review of Pharmacology and Toxicology |volume=37 |pages=167–203 |year=1997 |pmid=9131251 |doi=10.1146/annurev.pharmtox.37.1.167}}</ref> When activated, a heterotrimeric G protein dissociates into activated, GTP-bound alpha subunit and separate beta-gamma subunit, each of which can perform distinct signaling roles.<ref name="pmid3113327"/><ref name="pmid7579038"/> The α and γ subunit are modified by [[lipid anchor]]s to increase their association with the inner leaflet of the plasma membrane.<ref name="pmid11313912">{{cite journal |last1=Chen |first1=CA |last2=Manning |first2=DR |date=2001 |title=Regulation of G proteins by covalent modification |journal=Oncogene |volume=20 |issue=13 |pages=1643–1652 |doi=10.1038/sj.onc.1204185 |pmid=11313912 |doi-access=free }}</ref>

Heterotrimeric G proteins act as the transducers of [[G protein-coupled receptor]]s, coupling receptor activation to downstream signaling effectors and [[second messenger]]s.<ref name="pmid3113327"/><ref name="pmid7579038"/><ref name="pmid12209124">{{cite journal |last1=Pierce |first1=KL |last2=Premont |first2=RT |last3=Lefkowitz |first3=RJ |date=2002 |title=Seven-transmembrane receptors |journal= Nature Reviews Molecular Cell Biology|volume=3 |issue=9 |pages=639–650 |doi=10.1038/nrm908 |pmid=12209124 |s2cid=23659116 }}</ref> In unstimulated cells, heterotrimeric G proteins are assembled as the GDP bound, inactive trimer (G<sub>α</sub>-GDP-G<sub>βγ</sub> complex).<ref name="pmid3113327"/><ref name= "pmid7579038"/> Upon receptor activation, the activated receptor intracellular domain acts as GEF to release GDP from the G protein complex and to promote binding of GTP in its place.<ref name="pmid3113327"/><ref name="pmid7579038"/> The GTP-bound complex undergoes an activating conformation shift that dissociates it from the receptor and also breaks the complex into its component G protein alpha and beta-gamma subunit components.<ref name="pmid3113327"/><ref name="pmid7579038"/> While these activated G protein subunits are now free to activate their effectors, the active receptor is likewise free to activate additional G proteins – this allows catalytic activation and amplification where one receptor may activate many G proteins.<ref name="pmid3113327"/><ref name="pmid7579038"/>

G protein signaling is terminated by hydrolysis of bound GTP to bound GDP.<ref name="pmid3113327"/><ref name="pmid7579038"/> This can occur through the intrinsic GTPase activity of the α subunit, or be accelerated by separate regulatory proteins that act as [[GTPase-activating protein]]s (GAPs), such as members of the [[Regulator of G protein signaling]] (RGS) family).<ref name="pmid9430654"/> The speed of the hydrolysis reaction works as an internal clock limiting the length of the signal. Once G<sub>α</sub> is returned to being GDP bound, the two parts of the heterotrimer re-associate to the original, inactive state.<ref name="pmid3113327"/><ref name="pmid7579038"/>

The heterotrimeric G proteins can be classified by [[sequence homology]] of the α unit and by their functional targets into four families: G<sub>s</sub> family, G<sub>i</sub> family, G<sub>q</sub> family and G<sub>12</sub> family.<ref name="pmid10819326"/> Each of these G<sub>α</sub> protein families contains multiple members, such that the mammals have 16 distinct <sub>α</sub>-subunit genes.<ref name="pmid10819326"/> The G<sub>β</sub> and G<sub>γ</sub> are likewise composed of many members, increasing heterotrimer structural and functional diversity.<ref name="pmid10819326"/> Among the target molecules of the specific G proteins are the second messenger-generating enzymes [[adenylyl cyclase]] and [[phospholipase C]], as well as various [[ion channel]]s.<ref name="pmid12040175">{{cite journal |last1=Neves |first1=SR |last2=Ram |first2=PT |last3=Iyengar |first3=R |date=2002 |title=G protein pathways |journal=Science |volume=296 |issue=5573 |pages=1636–1639 |doi=10.1126/science.1071550 |pmid=12040175 |bibcode=2002Sci...296.1636N |s2cid=20136388 }}</ref>