@article{2404aa0d1b2741a381b749c4221b00fb,
title = "Nicotinamide mononucleotide adenylyl transferase uses its NAD+ substrate-binding site to chaperone phosphorylated TAU",
abstract = "Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer{\textquoteright}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.",
author = "Xiaojuan Ma and Yi Zhu and Jinxia Lu and Jingfei Xie and Chong Li and Shin, {Woo Shik} and Jiali Qiang and Jiaqi Liu and Shuai Dou and Yi Xiao and Chuchu Wang and Chunyu Jia and Houfang Long and Juntao Yang and Yanshan Fang and Lin Jiang and Yaoyang Zhang and Shengnan Zhang and Zhai, {Rong Grace} and Cong Liu and Dan Li",
note = "Funding Information: We thank Dr. Zhijun Liu, Dr. Songzi Jiang and other staff members of the National Center for Protein Science Shanghai for assistance in NMR data collection. This work was supported by the National Natural Science Foundation (NSF) of China (91853113 to D Li and C Liu), the Major State Basic Research Development Program (2016YFA0501902 to C Liu), the Science and Technology Commission of Shanghai Municipality (18JC1420500to C Liu), Shanghai Pujiang Program (18PJ1404300to D Li), the “Eastern Scholar” project supported by Shanghai Municipal Education Commission (to D Li), Shanghai Municipal Science and Technology Major Project (2019SHZDZX02to C Liu), and Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-02-E00037to D Li). The support also comes from Dr. John T Macdonald Foundation (to C Li), the Lois Pope LIFE fellows Program (to C Li and Y Zhu), NIH grant R56NS095893 and R61AT010408 (to RG Zhai). Funding Information: National Natural Science Foundation of China",
year = "2020",
month = apr,
doi = "10.7554/eLife.51859",
language = "English (US)",
volume = "9",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}