Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) "autonomous" activation induced by Thr286 phosphorylation has a crucial role in synaptic plasticity. Previous studies showed that in Alzheimer's disease brain, CaMKIIα autophosphorylation at Thr286 is reduced while the level of cysteine-oxidized CAMKIIα is elevated. We performed tryptic mapping of the oxidized CaMKIIα and discovered the formation of a disulfide between the N-terminal Cys6 and the regulatory domain Cys280. The apparent pKa values of Cys6 and Cys280 are 7.1 and 7.7, respectively, lower than the 8.5 for free Cys. The low apparent pKa of Cys6 facilitates the oxidation of its thiol to the sulfenic acid at physiological pH. The thiolate of Cys280 can then attack the sulfenic acid to form a disulfide. Using an antibody against phosphorylated Thr286, we showed that disulfide formation prevents Thr286 phosphorylation. CaMKIIα autonomous activation induced by disulfide formation is much lower than the autonomous activation induced by phosphorylation. The decreased autonomous activation may contribute to the synaptic impairment of Alzheimer's disease. We also generated a CaMKIIα mutant in which Cys6 was mutated to Ser6. This mutation prevented disulfide formation and restored autonomous activation induced by phosphorylation. Our findings provide insight into the mechanistic details of CaMKIIα autonomous activation induced by disulfide formation that may contribute to the impairment of long-term potentiation in Alzheimer's disease.

Nathália Rocco-Machado

Max Deng

Yi He

Rodney L Levine

Archives of Biochemistry and Biophysics

生物化学和生物物理学档案在生物化学和生物物理学的发展领域发表高质量的原创文章和评论。研究领域包括：• 酶和蛋白质的结构、功能、调控。折叠、周转和翻译后加工• 生物氧化、自由基反应、氧化还原信号、加氧酶、P450 反应• 信号转导、受体、膜转运、细胞内信号。细胞和综合代谢。

The Archives of Biochemistry and Biophysics is a journal dedicated to the fields of biochemistry and biophysics, publishing high-quality original research articles and reviews. The areas of research include: the structure, function, and regulation of enzymes and proteins; folding, turnover, and post-translational modifications; biological oxidation, free radical reactions, redox signaling, oxygenases, and P450 reactions; signal transduction, receptors, membrane transport, and intracellular signaling; as well as cellular and integrated metabolism.

《Archives of Biochemistry and Biophysics》是一个专注于生物化学和生物物理学领域的期刊，发表高质量的原创研究文章和评论。研究领域包括：酶和蛋白质的结构、功能及调控；折叠、周转和翻译后加工；生物氧化、自由基反应、氧化还原信号、加氧酶及P450反应；信号转导、受体、膜转运和细胞内信号；细胞及综合代谢。

Category	Quartile
生物学	3
生物学, 生物物理	2
生物学, 生化与分子生物学	3

Oxidation of CaMKIIα cysteines inhibits autonomous activation induced by phosphorylation

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