Hu Mengxue, Wang Fuxing, Zhu Yue, Yao Yi, Pei Huadong, Liu Zheng, Zhang Pingfeng
Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
School of Medicine, Kobilka Institute of Innovative Drug Discovery, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China.
Genes Dis. 2025 Jan 7;12(4):101510. doi: 10.1016/j.gendis.2024.101510. eCollection 2025 Jul.
Nicotinamide adenine dinucleotide (NAD) kinase (NADK) phosphorylates NAD to generate NADP, which plays a crucial role in maintaining NAD/NADP homeostasis, cellular redox balance, and metabolism. However, how human NADK activity is regulated, and how dysregulation or mutation of NADK is linked to human diseases, such as cancers, are still not fully understood. Here, we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity. The N-terminal region of human NADK, which does not exist in bacterial NADKs, modulates tetramer conformation, thereby regulating its activity. A methylation-deficient mutant, R45H, within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance. Conversely, mutations in NADK identified among cancer patients alter the tetramer conformation, resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy. Our findings partially unveil the structural basis for NADK regulation, offering insights into the cancer etiology of patients carrying NADK mutations.
烟酰胺腺嘌呤二核苷酸（NAD）激酶（NADK）将NAD磷酸化以生成NADP，NADP在维持NAD/NADP稳态、细胞氧化还原平衡和代谢中起关键作用。然而，人类NADK活性是如何被调控的，以及NADK的失调或突变如何与人类疾病（如癌症）相关联，目前仍未完全清楚。在此，我们展示了人类四聚体NADK的冷冻电镜结构，并阐述了NADK四聚体对其活性的必要性。人类NADK的N端区域不存在于细菌NADK中，它调节四聚体构象，从而调控其活性。N端区域内的一个甲基化缺陷突变体R45H导致NADK活性增加并赋予癌症化疗抗性。相反，在癌症患者中鉴定出的NADK突变会改变四聚体构象，导致NADK失活并增加肺癌细胞对化疗的敏感性。我们的研究结果部分揭示了NADK调控的结构基础，为携带NADK突变的患者的癌症病因提供了见解。
