Elevated copper ion levels as potential cause of impaired kinesin-dependent transport processes.
Copper is a trace element required to maintain essential life processes. In healthy organisms, copper metabolism is well balanced. If this balance is destroyed, the cellular level of free copper might increase and cause toxic effects. So far, the molecular mechanisms of copper intoxication are understood only partly. The present study revealed that the kinesin-dependent transport system is strongly affected by copper(II) ions. Both the microtubules, along which kinesin moves, and the kinesin itself were found to be the target structures of copper ions: Microtubule formation was suppressed by copper ions (IC50 26-70 µM) apparently chiefly by inhibition of binding of microtubule-associated proteins to tubulin. This inhibition could be widely compensated by the microtubule-stabilising agent paclitaxel. In addition, copper ions strongly inhibited the ATPase activity of neuron-specific kinesin KIF5A. At final KIF5A concentration of 112 nM, an IC50 of 1.3 µM was determined. Correspondingly, the motility activity of KIF5A, measured as velocity of microtubules gliding across a kinesin-covered surface, was blocked. The effects of copper ions on microtubules and on KIF5A are suggested to contribute to impaired transport processes within brain and other organs in cases of copper ion surplus.
Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstraße 11, 07745, Jena, Germany, kboehm@fli-leibniz.de.
Konrad J
KJ
Böhm
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000235:genetics; D016547:Kinesins / Q000737:chemistry* / Q000235:genetics; D008870:Microtubules / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport; D013552:Swine; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology
C500506:KIF5A protein, human; D050257:Tubulin Modulators; D003300:Copper; D016547:Kinesins; D017239:Paclitaxel; C029892:cupric chloride