GTPase activity

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

In summary, structural studies of Ras and Gq with GTP-yS and a transition state analog have illuminated the catalytic mechanism of their GTPase activity, as well as the mechanism by which GTP hydrolysis is stimulated by GAP and RGS. In addition, these structural studies have shown how tumor-causing mutations affect the function of Ras and Gq. 

Rittinger, K. et al. Crystal structure of a small G protein in complex with GTPase-activating protein rhoGAP. Nature 388 693-697, 1997. 

Rittinger, K., et al. Structure at 1.65 A of RhoA and its GTPase-activating protein in complex with a transition-state analogue. Nature 389 758-762, 1997. 

Scheffzek, K., et al. The Ras-RasGAP complex structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277 333-338, 1997. 

FIGURE 15.21 Hormone (H) binding to its receptor (R) creates a hormone receptor complex (H R) that catalyzes GDP-GTP exchange on the o -subunit of the heterotrimer G protein (G ), replacing GDP with GTP. The G -subunit with GTP bound dissociates from the /37-subunits and binds to adenylyl cyclase (AC). AC becomes active upon association with G GTP and catalyzes the formation of cAMP from ATP. With time, the intrinsic GTPase activity of the G -subunit hydrolyzes the bound GTP, forming GDP this leads to dissociation of G GDP from AC, reassociation of G with the /Sy subunits, and cessation of AC activity. AC and the hormone receptor H are integral plasma membrane proteins G and G are membrane-anchored proteins. 

G-proteins, trim eric membrane-bound proteins that have intrinsic GTPase activity and act as intermediaries between 7TM receptors and a host of cellular effectors see Section 2.2. 

Adaptor Proteins. Figure 1 Adaptor protein domains. A scheme of the domain structures of some well-characterized adaptor proteins is shown. Descriptions of domain characteristics are in main text except C2, binds to phospholipids GTPase activating protein (GAP) domain, inactivates small GTPases such as Ras Hect domain, enzymatic domain of ubiquitin ligases and GUK domain, guanylate kinase domain. For clarity, not all domains contained within these proteins are shown. 

GTPase activating proteins (GAPs) stimulate the intrinsic GTP hydrolysis of GTPases. 

Weiner CP, Mason CW, Buhimschi C, Hall G, Swaan PW, Buhimschi I. Changes in uterine GTPase activity are not consistent with changes in expression of Ga subunits of heterotrimeric G-proteins A potential mechanism for myometrial quiescence. Society of Gynecological Investigation. Los Angeles, CA, 2005. 

The ttj protein has inttinsic GTPase activity. The active fotm, (Xs GTP, is inactivated upon hydrolysis of the GTP to GDP the ttimetic G complex (apy) is then te-fotmed and is ready fot anothet cycle of activation. Gholeta and pettussis toxins catalyze the ADP-tibosylation of OL, and aj.2 (see Table 43-3), tespec-... 

Low concentrations of solubilised jS-albumin inhibit ACh release in slices from rat hippocampus and cortex areas which show degeneration in AzD, but not in slices from the striatum which is unaffected. While not totally specific to ACh, since some inhibition of NA and DA and potentiation of glutamate release have been reported, this effect is achieved at concentrations of A/i below those generally neurotoxic. Since jS-amyloid can inhibit choline uptake it is also possible (see Auld, Kar and Quiron 1998) that in order to obtain sufficient choline for ACh synthesis and the continued function of cholinergic neurons, a breakdown of membrane phosphatidyl choline is required leading to cell death (so-called autocannibalism), /i-amyloid can also reduce the secondary effects of Mi receptor activation such as GTPase activity... 

GAP GTPase-activating protein GBM Glomerular basement membrane... 

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