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Review
. 2009;17(1):82-99.
doi: 10.1159/000186692. Epub 2009 Feb 12.

Structural determinants involved in the formation and activation of G protein betagamma dimers

William E McIntire  1
Affiliations
Review

Structural determinants involved in the formation and activation of G protein betagamma dimers

William E McIntire. Neurosignals. 2009.

Abstract

Heterotrimeric G proteins, composed of an alpha, beta and gamma subunit, represent one of the most important and dynamic families of signaling proteins. As a testament to the significance of G protein signaling, the hundreds of seven-transmembrane-spanning receptors that interact with G proteins are estimated to occupy 1-2% of the human genome. This broad diversity of receptors is echoed in the number of potential heterotrimer combinations that can arise from the 23 alpha subunit, 7 beta subunit and 12 gamma subunit isoforms that have been identified. The potential for such vast complexity implies that the receptor G protein interface is the site of much regulation. The historical model for the activation of a G protein holds that activated receptor catalyzes the exchange of GDP for GTP on the alpha subunit, inducing a conformational change that substantially lowers the affinity of alpha for betagamma. This decreased affinity enables dissociation of betagamma from alpha and receptor. The free form of betagamma is thought to activate effectors, until the hydrolysis of GTP by G alpha (aided by RGS proteins) allows the subunits to re-associate, effectively deactivating the G protein until another interaction with activated receptor.

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Figures

Fig. 1
Fig. 1
Clam shell model of G protein opening after activation using the crystal structure of Wall et al. [45] . Left structure : Relationship of inactive GDP-bound form of Gi1 αβ1γ2 to the plasma membrane, with stylized lipids added to the structure. Right structure: βγ is in same conformation, but Gi1 α has been rotated approximately 90° counterclockwise; note that although lipids maintain their proximity, the face of the β propeller and switch I and II regions of Gi1 α, both occluded at left, are now sterically free to interact with effectors, and are thus ‘active’. (Although the same structure was used for simplicity, a truly active Gi1 α would have conformational changes in the switch regions, and GTPγS bound instead of GDP.)
Fig. 2
Fig. 2
Effect of different βγ isoforms on A2a adenosine receptor signaling. β1γ2 couples Gs α poorly to the A2a receptor, leading to lower activation of adenylyl cyclase; increasing levels of β4γ2, which couples Gs α more efficiently to the A2a receptor, increases adenylyl cyclase activation and intracellular cAMP levels.
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