eLife (Apr 2020)
Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau
- Xiaojuan Ma,
- Yi Zhu,
- Jinxia Lu,
- Jingfei Xie,
- Chong Li,
- Woo Shik Shin,
- Jiali Qiang,
- Jiaqi Liu,
- Shuai Dou,
- Yi Xiao,
- Chuchu Wang,
- Chunyu Jia,
- Houfang Long,
- Juntao Yang,
- Yanshan Fang,
- Lin Jiang,
- Yaoyang Zhang,
- Shengnan Zhang,
- Rong Grace Zhai,
- Cong Liu,
- Dan Li
Affiliations
- Xiaojuan Ma
- ORCiD
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Yi Zhu
- ORCiD
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States
- Jinxia Lu
- Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- Jingfei Xie
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Chong Li
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States
- Woo Shik Shin
- Department of Neurology, Molecular Biology Institute, and Brain Research Institute, University of California, Los Angeles, Los Angeles, United States
- Jiali Qiang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Jiaqi Liu
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China
- Shuai Dou
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Yi Xiao
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Chuchu Wang
- ORCiD
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Chunyu Jia
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Houfang Long
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China
- Juntao Yang
- State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Yanshan Fang
- ORCiD
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Lin Jiang
- ORCiD
- Department of Neurology, Molecular Biology Institute, and Brain Research Institute, University of California, Los Angeles, Los Angeles, United States
- Yaoyang Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Shengnan Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Rong Grace Zhai
- ORCiD
- Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United States
- Cong Liu
- ORCiD
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- Dan Li
- ORCiD
- Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- DOI
- https://doi.org/10.7554/eLife.51859
- Journal volume & issue
-
Vol. 9
Abstract
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.
Keywords
