The Lever Arm Model

This model was the first to be proposed based on the structures of various G protein heterotrimers as well as insights from (disease-causing) mutations [11]. In the lever-arm model (Fig. 4.1b), the GDP exit pathway is positioned in the area formed by the so-called switch regions 1 and 2 (switch regions are those portions of Ga that differ in conformation between the inactive GDP-liganded and the GTP- liganded active form). The model posits that GPy is the go -between that opens the GDP exit pathway in response to receptor activation: GPy covers a hydrophobic cavity between switches 1 and 2 and contacts the N-terminus of Ga [12,13]. The lever in the model proposed is this N-terminal helix (Na in Fig. 4.1b). This lever is operated by the activated receptor which displaces (and rotates) GPy relative to Ga. The resulting traction causes movement in switch 1 and in particular switch 2 and thus allows for GDP exit. The extensive contacts of GPy and Ga stabilize the GDP-free state of Ga, which is notorious for its instability. In fact, the ternary complex (HRG) of agonist (H)-liganded receptor (R) and guanine nucleotide-free G protein het-erotrimer (G) is amazingly stable. This model predicts that a manipulation that favors tilting of Ga in the heterotrimer ought to facilitate G protein activation. This prediction has been verified by using a mutant of Gas (the a subunit that stimulates adenylyl cyclase isoforms): if the N - l erminal helix of Gas is shortened by one helical turn (i.e., truncated by four amino acids) on its end adjacent to the RAS-like domain, activation of Gas by GPy is facilitated [14]. However, it still requires an inductive leap to extrapolate this effect of GPy to the action of the receptor. In fact, in the presence of high Mg2+ concentrations, GPy facilitates GDP release from Ga by a mechanism that is poorly understood [6]. It is not clear if this action has any relevance to the GEF action of GPCRs.

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