Cysteine oxidation of tau and microtubule-associated protein-2 by peroxynitrite: modulation of microtubule assembly kinetics by the thioredoxin reductase system.
Alterations in the redox status of proteins have been implicated in the pathology of several neurodegenerative conditions including Alzheimer and Parkinson diseases. We report that peroxynitrite- and hydrogen peroxide-induced disulfides in the neuron-specific microtubule-associated proteins tau and microtubule-associated protein-2 are substrates for the ubiquitous thioredoxin reductase system composed of thioredoxin reductase, human or Escherichia coli thioredoxin, and NADPH. Tau and microtubule-associated protein-2 cysteine oxidation and reduction were quantitated by monitoring the incorporation of 5-iodoacetamidofluorescein, a thiol-specific labeling reagent. Cysteine oxidation of tau and microtubule-associated protein-2 to disulfides altered the ability of the proteins to promote the assembly of microtubules from purified porcine tubulin. Treatment of tau and microtubule-associated protein-2 with either the thioredoxin reductase system or small molecule reductants fully restores the ability of the MAPs to promote microtubule assembly. Thus changes in the redox state of microtubule-associated proteins may regulate microtubule polymerization in vivo.
Landino
Lisa M
LM
Department of Chemistry, The College of William and Mary, Williamsburg, VA 23187-8795, USA. lmland@wm.edu
Skreslet
Tabor E
TE
Alston
Jane A
JA
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry*; D004220:Disulfides / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008956:Models, Chemical; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine; D013696:Temperature; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D004220:Disulfides; D005452:Fluoresceins; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D030421:Peroxynitrous Acid; D013879:Thioredoxins; C015296:5-iodoacetamidofluorescein; D013880:Thioredoxin-Disulfide Reductase; D003545:Cysteine; D010100:Oxygen