INHIBITION OF THE GDP GTP EXCHANGE-REACTION OF RAS P21 BY ALUMINUM ION/

In an effort to understand the biochemical mechanisms of aluminium-ind uced neurotoxicity, we investigated the effects of aluminum ion, Al3+, on the Mg2+- and nucleotide-dependent protein, ras p21. Picomolar Al3 + concentrations inhibited the GTPase activity of ras p21 in an Mg2+-d ependent manner, consistent with an Al3+/Mg2+ competition mechanism. G TPase activity was inhibited by 60% in the presence of 100 mu M Mg2+ a nd 2.9 X 10(-10) M Al3+. Kinetic studies demonstrated that the mode of Al3+-induced inhibition of ras p21 GTPase activity changed from compe titive to mixed noncompetitive as the number of ras p21 turnovers incr eased. Further dissection of the ras p21 cycle revealed that Mg2+-depe ndent GDP/GTP exchange was the Al3+-sensitive step. (C) 1997 Elsevier Science Inc.