GTPase Switch function

The members of the GTPase superfamily show an extensively conserved reaction mechanism. A common trait is a switching function that enables a reaction chain to be switched on or off (review Bourne et al., 1990). 

The switch function of the GTPase is based on the specific ability of the different functional states of the GTPase to interact with the proteins that precede and follow in the signal chain. A particular GTPase is characterized by the proteins with which the active and inactive forms interact. A special characteristic of the active GTP form is that it may activate effector enzymes further on in the reaction chain, e.g., adenylyl cyclase, and thus actively transmits the signal. 

Ras protein, the GTPase switch protein that functions in transducing signals from many different RTKs. The transduction of signals downstream from Ras to a common cascade of serlne/threonlne kinases, leading ultimately to activation of MAP kinase and certain transcription factors, is covered in the following section. 

All the residues involved in important functions in the catalytic mechanism are strictly conserved in all homologous GTPases with one notable exception. Ras does not have the arginine in the switch 1 region that stabilizes the transition state. The assumption that the lack of this catalytically important residue was one reason for the slow rate of GTP hydrolysis by Ras was confirmed when the group of Alfred Wittinghofer, Max-Planck Institute,... 

The regulatory GTPases function as switches that can exist in an active or inactive form. In the active form the GTPases can transmit signals to downstream components in the signaling chain. In the inactive form signal transmission in repressed. 

Bourne, H.R., Sanders, D.A. and McCormick, F. The GTPase superfamily a conserved switch for diverse cell functions (1990) Nature 348, 125-132... 

Cholera is a condition caused by a protein exotoxin produced by the bacterium vibrio cholerae. This protein toxin consists of six subunits one A subunit and five B subunits. The B subunits are responsible for the binding of the toxin to cAMP-functioning cells in small bowel of the intestines. The A subunit penetrates the cell and has catalytic activity which attaches the ADP portion of naturally occurring NAD (nicotine-adenosine dinucleotide) to the G-protein complex thereby inhibiting its GTPase activity. This deprives the complex of its "off-switch" for cAMP formation. The effect is the uncontrolled... 

Reprinted with permission from Nature (H. R. Bourne et al., The GTPase superfamily A conserved switch of diverse cell functions, Nature, 348 126, 1990). Copyright 1990 Macmillan Magazines Limited.)... 

Ras is the master controller of a central cellular signalling pathway, the MAP kinase-phosphorylation cascade. Ras accomplishes its regulatory role in a way that is different from the function of the other regulatory components of signalling networks discussed up to now. Ras is a GTPase. In the GTP-bound state its activity is switched on and in the GDP-bound state, switched off. 

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