Nicotinamide mononucleotide adenylyltransferase 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'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 en

SUBMITTER: Ma X 

PROVIDER: S-EPMC7136026 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature