Nicotinamide mononucleotide adenylyl transferase 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 LiuDan Li

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article numbere51859
StatePublished - Apr 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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