Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau
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 progressio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/51859 |
| _version_ | 1811228059668316160 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaojuan Ma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:52:09Z |
| format | Article |
| id | doaj.art-7a6c38a74c5f4d10ba956531826059aa |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:52:09Z |
| publishDate | 2020-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7a6c38a74c5f4d10ba956531826059aa2022-12-22T03:37:48ZengeLife Sciences Publications LtdeLife2050-084X2020-04-01910.7554/eLife.51859Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated TauXiaojuan Ma0https://orcid.org/0000-0003-2682-0501Yi Zhu1https://orcid.org/0000-0002-1778-8880Jinxia Lu2Jingfei Xie3Chong Li4Woo Shik Shin5Jiali Qiang6Jiaqi Liu7Shuai Dou8Yi Xiao9Chuchu Wang10https://orcid.org/0000-0003-2015-7331Chunyu Jia11Houfang Long12Juntao Yang13Yanshan Fang14https://orcid.org/0000-0002-4123-0174Lin Jiang15https://orcid.org/0000-0003-3039-1877Yaoyang Zhang16Shengnan Zhang17Rong Grace Zhai18https://orcid.org/0000-0002-7599-1430Cong Liu19https://orcid.org/0000-0003-3425-6672Dan Li20https://orcid.org/0000-0002-1609-1539Interdisciplinary 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, ChinaDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United StatesBio-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, ChinaInterdisciplinary 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, ChinaDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United StatesDepartment of Neurology, Molecular Biology Institute, and Brain Research Institute, University of California, Los Angeles, Los Angeles, United StatesInterdisciplinary 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, ChinaSchool 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, ChinaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaInterdisciplinary 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, ChinaInterdisciplinary 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, ChinaInterdisciplinary 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, ChinaState 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, ChinaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Neurology, Molecular Biology Institute, and Brain Research Institute, University of California, Los Angeles, Los Angeles, United StatesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, United StatesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaBio-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, ChinaTau 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.https://elifesciences.org/articles/51859Alzheimer's diseasetauopathyphosphorylated TauchaperoneNMNATNAD synthase |
| spellingShingle | 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 Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau eLife Alzheimer's disease tauopathy phosphorylated Tau chaperone NMNAT NAD synthase |
| title | Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau |
| title_full | Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau |
| title_fullStr | Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau |
| title_full_unstemmed | Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau |
| title_short | Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau |
| title_sort | nicotinamide mononucleotide adenylyltransferase uses its nad substrate binding site to chaperone phosphorylated tau |
| topic | Alzheimer's disease tauopathy phosphorylated Tau chaperone NMNAT NAD synthase |
| url | https://elifesciences.org/articles/51859 |
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