G-protein linked receptors activate G proteins by reducing the strength of GDP binding. This results in rapid dissociation of bound GDP, which is then replaced by GTP, which is present in the cytosol in much higher concentrations than GDP. What consequences would result from a mutation in the alpha subunit of the G protein that caused its affinity for GDP to be reduced without significantly changing its affinity for GTP? Compare the effects of this mutation with the effects of cholera toxin.© BrainMass Inc. brainmass.com December 24, 2021, 10:37 pm ad1c9bdddf
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A mutation in which the alpha subunit that causes a reduced affinity in association with GDP without changing its affinity for GTP would result in signaling through G-protein receptors constitutively active. This means that intracellular signaling of the heterotrimetic G-proteins would be independent of ligand binding to its receptor. This is because the ligand binding to the receptor causes a conformational change in the G-protein linked receptors causing the reduction in the alpha subunit's affinity for the GDP molecule. This allows the alpha subunit to now bind GTP and induce intracellular signaling. This process would not require the receptors
If the alpha subunit had a mutation in which the affinity of GDP is reduced without a change in the affinity for GTP, then the alpha subunit would dissociate from GDP molecules independent of signaling by the receptor. You would still have many more GTP molecules than GDP molecules so the alpha subunit would bind GTP and induce intracellular signaling. The problem is that now intracellular signaling would be independent of receptor binding at the surface of the cell. If the mutation significant enough, as soon as GTP is converted to GDP, the alpha subunit would lose its affinity for the GDP and the alpha subunit would immediately bind a new GTP molecule and intracellular signaling would not be controlled. It would be constitutively active.
Cholera toxin would have the same effect, but with a different mechanism. Here cholera toxin stimulates the alpha subunit but locks the alpha subunit into the active state. It does this by an ADP-ribosylation reaction that inhibits cleavage of GTP to GDP. This is achieved by inhibiting the GTPase enzyme from converting GTP to GDP. In the case of mutation described above and chloera toxin both lead to signaling independent of receptors but use slightly different changes to the alpha subunit. In the case of the mutation it is that the alpha subunit can't bind the GDP molecule very well allowing the subunit to be stimulated and in the case of cholera toxin the alpha subunit does not convert GTP to GDP allowing the subunit to be really active. Between the two mechanisms, cholera toxin probably will induce a longer constitutively active state because you cannot produce GDP to turn off the pathway. However if the mutation is strong enough, alpha subunit will not be able to bind GDP well at all and so the subunit spent almost all of its time bound to GTP.© BrainMass Inc. brainmass.com December 24, 2021, 10:37 pm ad1c9bdddf>