Nicotinamide mononucleotide adenylyltransferase uses its NAD + substrate-binding site to chaperone phosphorylated Tau

• Published in: eLife 2020-04, Vol.9
• Main Authors: Ma, Xiaojuan, Zhu, Yi, Lu, Jinxia, Xie, Jingfei, Li, Chong, Shin, Woo Shik, Qiang, Jiali, Liu, Jiaqi, Dou, Shuai, Xiao, Yi, Wang, Chuchu, Jia, Chunyu, Long, Houfang, Yang, Juntao, Fang, Yanshan, Jiang, Lin, Zhang, Yaoyang, Zhang, Shengnan, Zhai, Rong Grace, Liu, Cong, Li, Dan
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer's disease; Amyloid; Animals; Binding Sites; Biochemistry and Chemical Biology; chaperone; Chaperones; Computational neuroscience; Crystallography; Drosophila; Enzymes; Homeostasis; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humans; Kinases; Magnetic resonance spectroscopy; Molecular Chaperones - physiology; NAD; NAD - metabolism; NAD synthase; Neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Nicotinamide; Nicotinamide-Nucleotide Adenylyltransferase - physiology; NMNAT; NMR; Nuclear magnetic resonance; phosphorylated Tau; Phosphorylation; Proteins; Synapses - physiology; Tau protein; tau Proteins - metabolism; tauopathy
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.51859

Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer's disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD metabolism and Tau homeostasis in aging and neurodegeneration.