| Structural highlights
Function
NMNA3_MOUSE Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency. Can use triazofurin monophosphate (TrMP) as substrate. Can also use GTP and ITP as nucleotide donors. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity, can use NAD(+), NADH, NaAD, nicotinic acid adenine dinucleotide phosphate (NHD), nicotinamide guanine dinucleotide (NGD) as substrates. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+) (By similarity). Protects against axonal degeneration following injury.[UniProtKB:Q96T66][1]
Publication Abstract from PubMed
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.
Nicotinamide mononucleotide adenylyltransferase uses its NAD(+) substrate-binding site to chaperone phosphorylated Tau.,Ma X, Zhu Y, Lu J, Xie J, Li C, Shin WS, 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 RG, Liu C, Li D Elife. 2020 Apr 6;9. pii: 51859. doi: 10.7554/eLife.51859. PMID:32250733[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006 Aug 16;26(33):8484-91. PMID:16914673 doi:10.1523/JNEUROSCI.2320-06.2006
- ↑ Ma X, Zhu Y, Lu J, Xie J, Li C, Shin WS, 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 RG, Liu C, Li D. Nicotinamide mononucleotide adenylyltransferase uses its NAD(+) substrate-binding site to chaperone phosphorylated Tau. Elife. 2020 Apr 6;9:e51859. PMID:32250733 doi:10.7554/eLife.51859
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