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

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Oncology

Background:

• Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) is vital for maintaining cellular redox balance and metabolism by producing NADP+.
• The precise regulation of human NADK and its link to diseases like cancer remain incompletely understood.

Purpose of the Study:

• To elucidate the structural basis of human NADK regulation and its role in cancer.
• To investigate the functional significance of the NADK tetramer and its N-terminal region.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of human tetrameric NADK.
• Analysis of NADK mutants, including R45H and patient-derived mutations, to assess their impact on activity and conformation.

Main Results:

• The study presents the cryo-EM structure of human tetrameric NADK, highlighting the tetramer's necessity for enzymatic activity.
• The N-terminal region of human NADK, absent in bacterial forms, modulates tetramer conformation and activity.
• A methylation-deficient mutant (R45H) showed increased NADK activity and conferred chemotherapy resistance.
• Cancer patient-derived mutations altered tetramer conformation, leading to NADK inactivation and increased sensitivity of lung cancer cells to chemotherapy.

Conclusions:

• Human NADK activity is regulated by its N-terminal region and tetramer conformation.
• NADK dysregulation and mutations have significant implications for cancer development and treatment response.
• These findings provide structural insights into NADK regulation and its connection to cancer etiology.