Kinesin-dependent motility generation as target mechanism of cadmium intoxication.
The anterograde vesicle transport within neurons critically depends on microtubules and on the activity of kinesin. The present study demonstrates that cadmium ions inhibit the in vitro assembly of microtubules from tubulin, whereby at high cadmium levels (∼500 μM) unstructured protein aggregates were formed. Cadmium ions also significantly lower both the ATPase and motility activity of neuron-specific kinesin KIF5A in concentration-dependent manner. For the inhibition of KIF5A ATPase activity, an IC50 value of 10.4±1.5 μM was determined. Inhibition could be widely compensated by addition of EGTA, but not by addition of thiols. The inhibitory effect of cadmium on KIF5A was considerably weakened by increasing ATP concentration. As nucleoside triphosphate binding is known to be accompanied by conformational changes within the kinesin motor domain, it might be suggested that these changes protect the motor domain against cadmium. The effects of cadmium ions on the kinesin-microtubule motility generating system are considered to contribute to the development of neuronal disorders caused by cadmium intoxication.
Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstraße 11, D-07745 Jena, Germany. Electronic address: kboehm@fli-leibniz.de.
Konrad J
KJ
Böhm
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D019256:Cadmium Chloride / Q000633:toxicity*; D002105:Cadmium Poisoning / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002474:Cell-Free System; D006801:Humans; D016547:Kinesins / Q000378:metabolism / Q000502:physiology*; D008870:Microtubules / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013552:Swine; D014404:Tubulin / Q000378:metabolism
C500506:KIF5A protein, human; D013438:Sulfhydryl Compounds; D014404:Tubulin; D000251:Adenosine Triphosphatases; D016547:Kinesins; D019256:Cadmium Chloride
ATPase; Cadmium; KIF5A; Kinesin; Motility; Tubulin