Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China; Bio-X-Renji Hospital Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; University of the Chinese Academy of Sciences, Beijing, China.
J Biol Chem. 2022 May;298(5):101912. doi: 10.1016/j.jbc.2022.101912. Epub 2022 Apr 7.
Molecular chaperones safeguard cellular protein homeostasis and obviate proteotoxicity. In the process of aging, as chaperone networks decline, aberrant protein amyloid aggregation accumulates in a mechanism that underpins neurodegeneration, leading to pathologies such as Alzheimer's disease and Parkinson's disease. Thus, it is important to identify and characterize chaperones for preventing such protein aggregation. In this work, we identified that the NAD synthase-nicotinamide mononucleotide adenylyltransferase (NMNAT) 3 from mouse (mN3) exhibits potent chaperone activity to antagonize aggregation of a wide spectrum of pathological amyloid client proteins including α-synuclein, Tau (K19), amyloid β, and islet amyloid polypeptide. By combining NMR spectroscopy, cross-linking mass spectrometry, and computational modeling, we further reveal that mN3 uses different region of its amphiphilic surface near the active site to directly bind different amyloid client proteins. Our work demonstrates a client recognition mechanism of NMNAT via which it chaperones different amyloid client proteins against pathological aggregation and implies a potential protective role for NMNAT in different amyloid-associated diseases.
分子伴侣可保护细胞内蛋白质的平衡，避免毒性蛋白聚集。在衰老过程中，由于伴侣网络的下降，异常蛋白淀粉样聚集物积累，这种机制是神经退行性疾病的基础，导致阿尔茨海默病和帕金森病等病理发生。因此，识别和鉴定具有预防此类蛋白聚集功能的伴侣是很重要的。在这项工作中，我们发现来自小鼠的烟酰胺核苷酸腺嘌呤二核苷酸合成酶-烟酰胺单核苷酸腺苷转移酶 3（mN3）具有很强的伴侣活性，可以拮抗广泛的病理淀粉样蛋白客户蛋白的聚集，包括α-突触核蛋白、Tau（K19）、淀粉样β和胰岛淀粉样多肽。通过结合 NMR 光谱学、交联质谱和计算建模，我们进一步揭示 mN3 利用其靠近活性位点的两亲性表面的不同区域直接结合不同的淀粉样客户蛋白。我们的工作展示了 NMNAT 通过该机制识别不同淀粉样客户蛋白的机制，该机制可防止其发生病理性聚集，并暗示 NMNAT 在不同的淀粉样相关疾病中具有潜在的保护作用。
