NADK tetramer defective mutants affect lung cancer response to chemotherapy via controlling NADK activity

TL;DR

This study explores how mutations in the NADK enzyme affect lung cancer's response to chemotherapy by altering its activity.

Contribution

The paper reveals the structural basis of NADK regulation and its role in chemotherapy resistance or sensitivity in lung cancer.

Findings

The N-terminal region of human NADK modulates tetramer conformation and regulates its activity.

The R45H mutation increases NADK activity and causes chemotherapy resistance in cancer cells.

Cancer-associated NADK mutations disrupt tetramer conformation, inactivate NADK, and increase chemotherapy sensitivity.

Abstract

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.

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