G alpha subunit

Guanine nucleotide binding proteins (G proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha, beta, and gamma.^[1] G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation.^[2] At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal.^[3] The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications.^[4]

There are several isoforms of each subunit, many of which have splice variants, which together can make up hundreds of combinations of G proteins. The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli.^[5]^[6] G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.

This family consists of the G protein alpha subunit, which acts as a weak GTPase. G protein classes are defined based on the sequence and function of their alpha subunits, which in mammals fall into several sub-types: G(S)alpha, G(Q)alpha, G(I)alpha, transducin and G(12)alpha; there are also fungal and plant classes of alpha subunits. The alpha subunit consists of two domains: a GTP-binding domain and a helical insertion domain (INTERPRO). The GTP-binding domain is homologous to Ras-like small GTPases, and includes switch regions I and II, which change conformation during activation. The switch regions are loops of alpha-helices with conformations sensitive to guanine nucleotides. The helical insertion domain is inserted into the GTP-binding domain before switch region I and is unique to heterotrimeric G proteins. This helical insertion domain functions to sequester the guanine nucleotide at the interface with the GTP-binding domain and must be displaced to enable nucleotide dissociation.

References

↑ Preininger AM, Hamm HE (February 2004). "G protein signaling: insights from new structures". Sci. STKE. 2004 (218): re3. doi:10.1126/stke.2182004re3. PMID 14762218.
↑ Roberts DJ, Waelbroeck M (September 2004). "G protein activation by G protein coupled receptors: ternary complex formation or catalyzed reaction?". Biochem. Pharmacol. 68 (5): 799–806. doi:10.1016/j.bcp.2004.05.044. PMID 15294442.
↑ Svoboda P, Teisinger J, Novotný J, Bourová L, Drmota T, Hejnová L, Moravcová Z, Lisý V, Rudajev V, Stöhr J, Vokurková A, Svandová I, Durchánková D (2004). "Biochemistry of transmembrane signaling mediated by trimeric G proteins". Physiol Res. 53 Suppl 1: S141–52. PMID 15119945.
↑ Chen CA, Manning DR (March 2001). "Regulation of G proteins by covalent modification". Oncogene. 20 (13): 1643–52. doi:10.1038/sj.onc.1204185. PMID 11313912.
↑ Hildebrandt JD (August 1997). "Role of subunit diversity in signaling by heterotrimeric G proteins". Biochem. Pharmacol. 54 (3): 325–39. doi:10.1016/S0006-2952(97)00269-4. PMID 9278091.
↑ Albert PR, Robillard L (May 2002). "G protein specificity: traffic direction required". Cell. Signal. 14 (5): 407–18. doi:10.1016/S0898-6568(01)00259-5. PMID 11882385.

This article incorporates text from the public domain Pfam and InterPro IPR001019

Intracellular signaling peptides and proteins

MAP

see MAP kinase pathway

Calcium

G protein

Heterotrimeric

cAMP:	Heterotrimeric G protein Gs/Gi Adenylate cyclase cAMP 3',5'-cyclic-AMP phosphodiesterase Protein kinase A

cGMP:	Transducin Gustducin Guanylate cyclase cGMP 3',5'-cyclic-GMP phosphodiesterase Protein kinase G

G alpha subunit G_α GNAO1 GNAI1 GNAI2 GNAI3 GNAT1 GNAT2 GNAT3 GNAZ GNAS GNAL GNAQ GNA11 GNA12 GNA13 GNA14 GNA15/GNA16

G beta-gamma complex G_β GNB1 GNB2 GNB3 GNB4 GNB5 G_γ GNGT1 GNGT2 GNG2 GNG3 GNG4 GNG5 GNG7 GNG8 GNG10 GNG11 GNG12 GNG13 BSCL2

G protein-coupled receptor kinase AMP-activated protein kinase

Monomeric

Cyclin

Lipid

Other protein kinase

Serine/threonine:	Casein kinase 1 2 eIF-2 kinase EIF2AK3 Glycogen synthase kinase GSK1 GSK2 GSK-3 GSK3A GSK3B IκB kinase CHUK IKK2 IKBKG Interleukin-1 receptor-associated kinase IRAK1 IRAK2 IRAK3 IRAK4 Lim kinase LIMK1 LIMK2 p21-activated kinases PAK1 PAK2 PAK3 PAK4 Rho-associated protein kinase ROCK1 ROCK2 Ribosomal s6 kinase RPS6KA1

Tyrosine:	ZAP70 Focal adhesion protein-tyrosine kinase PTK2 PTK2B BTK

both	Dual-specificity kinase

Other protein phosphatase

Serine/threonine:	Protein phosphatase 2

Tyrosine:	protein tyrosine phosphatase: Receptor-like protein tyrosine phosphatase Sh2 domain-containing protein tyrosine phosphatase

both:	Dual-specificity phosphatase

Apoptosis

see apoptosis signaling pathway

GTP-binding protein regulators

see GTP-binding protein regulators

Other

see also deficiencies of intracellular signaling peptides and proteins

Hydrolases: acid anhydride hydrolases (EC 3.6)

3.6.1

3.6.2

3.6.3-4: ATPase

3.6.3

Cu++ (3.6.3.4)	Menkes/ATP7A Wilson/ATP7B

Ca+ (3.6.3.8)	SERCA ATP2A1 ATP2A2 ATP2A3 Plasma membrane ATP2B1 ATP2B2 ATP2B3 ATP2B4 SPCA ATP2C1 ATP2C2

Na+/K+ (3.6.3.9)	ATP1A1 ATP1A2 ATP1A3 ATP1A4 ATP1B1 ATP1B2 ATP1B3 ATP1B4

H+/K+ (3.6.3.10)	ATP4A

Other P-type ATPase	ATP8B1 ATP10A ATP11B ATP12A ATP13A2 ATP13A3

3.6.4

3.6.5: GTPase

3.6.5.1: Heterotrimeric G protein	G_αs G_αi GNAI1 GNAI2 GNAI3 G_αq/11 GNAQ GNA11 G_α12/13 GNA12 GNA13 Transducin GNAT1 GNAT2 Gustducin GNAT3

3.6.5.2: Small GTPase > Ras superfamily	Rho family of GTPases: Cdc42 CDC42 TC10 TCL RhoUV RhoU RhoV Rac Rac1 2 3 RhoG RhoBTB 1 2 RhoH Rho A B C Rnd 1 2 3 RhoDF RhoF RhoD other: Ras HRAS KRAS NRAS Rab RAB23 RAB27 Arf ARF6 SAR1B ARL13B ARL6 Ran Rheb Rap RGK

3.6.5.3: Protein-synthesizing GTPase	Prokaryotic IF-2 EF-Tu EF-G Eukaryotic

3.6.5.5-6: Polymerization motors	Dynamin Tubulin

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

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