Nicotinamide mononucleotide adenylyltransferase uses its NAD + substrate-binding site to chaperone phosphorylated Tau
Authors
Lu, Jinxia
Xie, Jingfei
Li, Chong
Shin, Woo Shik
Qiang, Jiali
Liu, Jiaqi
Dou, Shuai
Xiao, Yi
Jia, Chunyu
Long, Houfang
Yang, Juntao
Zhang, Yaoyang
Zhang, Shengnan
Publication Date
2020-04-06Journal Title
eLife
Publisher
eLife Sciences Publications, Ltd
Volume
9
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Ma, X., Zhu, Y., Lu, J., Xie, J., Li, C., Shin, W. S., Qiang, J., et al. (2020). Nicotinamide mononucleotide adenylyltransferase uses its NAD + substrate-binding site to chaperone phosphorylated Tau. eLife, 9 https://doi.org/10.7554/elife.51859
Description
Funder: Science and Technology Commission of Shanghai Municipality; FundRef: http://dx.doi.org/10.13039/501100003399
Funder: Dr. John T. MacDonald Foundation; FundRef: http://dx.doi.org/10.13039/100010239
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
Research Article, Biochemistry and Chemical Biology, Alzheimer's disease, tauopathy, phosphorylated Tau, chaperone, NMNAT, NAD synthase, D. melanogaster
Sponsorship
National Natural Science Foundation of China (91853113)
Major State Basic Research Development Program (2016YFA0501902)
University of Miami (Lois Pope LIFE fellows Program)
National Institutes of Health (R56NS095893)
National Institutes of Health (R61AT010408)
Shanghai Pujiang Program (18PJ1404300)
Shanghai Municipal Science and Technology Major Project (2019SHZDZX02)
Shanghai Municipal Education Commission (Innovation Program 2019-01-07-00-02-E00037)
Shanghai Municipal Education Commission (“Eastern Scholar” project)
Identifiers
51859
External DOI: https://doi.org/10.7554/elife.51859
This record's URL: https://www.repository.cam.ac.uk/handle/1810/304169
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/