Quantitative Chemoproteomics Reveals Dopamine's Protective Modification of Tau

Dopamine (DA) is one of the most important neurotransmitters. Its oxidation leads to electrophilic quinone, which covalently modifies nucleophilic residues in proteins, resulting in ‘dopamination’. Individual dopaminated proteins have been studied, most of which were functionally damaged by dopamination. Here, we developed a quantitative chemoproteomic strategy to site-specifically measure proteins’ dopamination. More than 6,000 dopamination sites were quantified and IC50 values for 63 hyper-sensitive sites were measured. Among them, hyper-sensitive dopamination of two cysteines in microtubule-associated protein Tau were biochemically validated and functionally characterized to prevent Tau’s amyloid fibrillation and promote Tau-mediated assembly of microtubules. In addition, endogenous dopamination of Tau in mouse brain was detected through targeted mass spectrometry analysis. Our study not only provided the global portrait of dopamination, but also discovered a protective role of DA in regulating the function of Tau, which will enhance our understanding of physiological and pathological functions of DA in human brain.