5Z9R

NMNAT as a specific chaperone antagonizing pathological condensation of phosphorylated tau

Summary for 5Z9R

• Entry DOI: 10.2210/pdb5z9r/pdb
• Descriptor: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (2 entities in total)
• Functional Keywords: antagonizing pathological condensation of phosphorylated tau, chaperone, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 63145.95

Authors

Dou, S.,Ma, X.,Li, D.,Liu, C. (deposition date: 2018-02-05, release date: 2019-02-06, Last modification date: 2023-11-22)

Primary citation

Ma, X.,Zhu, Y.,Lu, J.,Xie, J.,Li, C.,Shin, W.S.,Qiang, J.,Liu, J.,Dou, S.,Xiao, Y.,Wang, C.,Jia, C.,Long, H.,Yang, J.,Fang, Y.,Jiang, L.,Zhang, Y.,Zhang, S.,Zhai, R.G.,Liu, C.,Li, D.
Nicotinamide mononucleotide adenylyltransferase uses its NAD+substrate-binding site to chaperone phosphorylated Tau.
Elife, 9:-, 2020

PubMed 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.

PubMed: 32250733
DOI: 10.7554/eLife.51859

Experimental method

X-RAY DIFFRACTION (2 Å)