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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Understanding the catalytic mechanism of GTPase-activating proteins: demonstration of the importance of switch domain stabilization in the stimulation of GTP hydrolysis.

Cdc42, a member of the Rho family of GTP-binding proteins, has been implicated in a variety of biological activities, including the organization of the actin cytoskeleton, changes in cell morphology and motility, intracellular trafficking, cell cycle progression, and cellular transformation. The cycling of Cdc42 between its on (GTP-bound) and off (GDP-bound) states is essential for its stimulation of cell growth and transformation, with an important aspect of this cycle being the regulation of the GTP hydrolytic activity of Cdc42 by its GTPase-activating protein (Cdc42GAP). On the basis of the structural determinations of the Cdc42-Cdc42GAP complex, as well as the Ras-RasGAP complex, it has been proposed that an arginine residue provided by the GAP (called the "arginine finger") stabilizes charges developing on the guanine nucleotide during the transition state for GTP hydrolysis and is an important contributor to GAP-stimulated catalysis. However, the 85 kDa regulatory subunit (p85) of the phosphoinositide 3-kinase ( PI-3K) is homologous with the Cdc42GAP and contains the essential arginine residue, but is ineffective as a GAP. This argues that the introduction of the arginine finger is insufficient for GAP activity and that the GAP must fulfill an additional function, one possibility being the engagement and stabilization of the conformationally sensitive switch regions of Cdc42. In the study presented here, we have tested this idea by examining three residues within the Cdc42GAP, which are missing in the GAP homology domain of the 85 kDa regulatory subunit (p85) of the PI 3-kinase and are involved in specific interactions with switch domain residues of Cdc42. We show that the mutation of all three residues, as well as individual mutations of each of these residues, yields GAPs that are defective in stimulating GTP hydrolysis. We further demonstrate that the switch I residue tyrosine 32 plays an important role in GAP interactions and in the regulation of both intrinsic and GAP-stimulated GTP hydrolysis. Taken together, these findings indicate that stabilizing the switch domains of GTP-binding proteins is an important part of GAP-stimulated catalysis, and that the inability of p85 to participate in these interactions may at least in part explain its ineffectiveness as a GAP.[1]


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