Signal Termination Through GAPs and Effector GAP Domains

Signal Termination Through GAPs and Effector GAP Domains 

When reconstituted into proteoliposomes with Ml muscarinic cholinergic receptor, PLC/11 potently stimulates the GTPase activity of Gaq, achieving a steady-state rate 1000-fold greater than that in the absence of a GAP 

The mechanism by which PLCjSl is stimulated by or exerts GAP activity toward Gaq/11 is unknown, and is likely to remain so until the structure of the complex can be determined. The C2 domain of PLCjSl, which is located between the catalytic and C-terminal domains of the enzyme, was shown to bind to GTPyS-activated Gaq (Wang et al., 1999). Thus, Gaq might act allosterically on the catalytic domains via contacts with C2 (Singer et al., 2002), perhaps using the C-terminus as a scaffold. 

Key to understanding the mechanism of RGS GAPs, and GAPs in general, is the observation that they bind most tightly to the GDP Mg2+ AlF 4 complex of their Ga substrates (Berman et al, 1996a Chen et al, 1996, 1997 Watson et al., 1996) and thereby promote a conformation that is structurally most 

To stabilize the catalytically active state of Ga, RGS domains distribute binding energy over the entire Ga interaction surface (Fig. 7B). Mutations at conserved residues in all three RGS4 contact zones impair GAP activity, and the effects of some of these mutations are thermodynamically additive (Chen et al., 1997 Natochin et al, 1998b Posner et al., 1999  

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V. Signal Termination Through GAPs and Effector GAP Domains. 38... 

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