Inhibition of the GDP/GTP exchange reaction of ras p21 by aluminium ion

Abstract

In an effort to understand the biochemical mechanisms of aluminum-induced neurotoxicity, we investigated the effects of aluminum ion, Al 3+, on the Mg 2+ - and nucleotide-dependent protein, ras p21. Picomolar Al 3+ concentrations inhibited the GTPase activity of ras p21 in an Mg 2+-dependent manner, consistent with an Al 3+/Mg 2+ competition mechanism. GTPase activity was inhibited by 60% in the presence of 100 μM Mg 2+ and 2.9 × 10 −10 M Al 3+. Kinetic studies demonstrated that the mode of Al 3+-induced inhibition of ras p21 GTPase activity changed from competitive to mixed non-competitive as the number of ras p21 turnovers increased. Further dissection of the ras p21 cycle revealed that Mg 2+-dependent GDP/GTP exchange was the Al 3+-sensitive step.