Cryo-EM structure and regulation of human NAD kinase

Prakash P Praharaj; Yang Li; Charline Mary; Mona H Soflaee; Kevin Ryu; Dohun Kim; Diem H Tran; Trishna Dey; Harrison J Tom; Halie Rion; Muriel Gelin; Andrew Lemoff; Lauren G Zacharias; João S Patricio; Thomas P Mathews; Zhe Chen; Corinne Lionne; Gerta Hoxhaj; Gilles Labesse

doi:10.1126/sciadv.ads2664

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Cryo-EM structure and regulation of human NAD kinase

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Cryo-EM structure and regulation of human NAD kinase

Prakash P Praharaj, Yang Li, Charline Mary, Mona H Soflaee, Kevin Ryu, Dohun Kim, Diem H Tran, Trishna Dey, Harrison J Tom, Halie Rion, …

Science advances, Vol.11(4), p.eads2664

24/01/2025

DOI: https://doi.org/10.1126/sciadv.ads2664

PMID: 39854463

Résumé

Cryoelectron Microscopy

Humans

Models, Molecular

NAD - chemistry

NAD - metabolism

NADP - metabolism

Phosphotransferases (Alcohol Group Acceptor) - chemistry

Phosphotransferases (Alcohol Group Acceptor) - genetics

Phosphotransferases (Alcohol Group Acceptor) - metabolism

Protein Binding

Protein Conformation

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a crucial reducing cofactor for reductive biosynthesis and protection from oxidative stress. To fulfill their heightened anabolic and reductive power demands, cancer cells must boost their NADPH production. Progrowth and mitogenic protein kinases promote the activity of cytosolic NAD kinase (NADK), which produces NADP , a limiting NADPH precursor. However, the molecular architecture and mechanistic regulation of human NADK remain undescribed. Here, we report the cryo-electron microscopy structure of human NADK, both in its apo-form and in complex with its substrate NAD (nicotinamide adenine dinucleotide), revealing a tetrameric organization with distinct structural features. We discover that the amino (N)- and carboxyl (C)-terminal tails of NADK have opposing effects on its enzymatic activity and cellular NADP(H) levels. Specifically, the C-terminal region is critical for NADK activity, whereas the N-terminal region exhibits an inhibitory role. This study highlights molecular insights into the regulation of a vital enzyme governing NADP(H) production.

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Titre: Cryo-EM structure and regulation of human NAD kinase
Créateurs - sans rôle: Prakash P Praharaj - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Yang Li - Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Charline Mary - Centre de Biologie Structurale
Mona H Soflaee - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Kevin Ryu - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Dohun Kim - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Diem H Tran - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Trishna Dey - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Harrison J Tom - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Halie Rion - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Muriel Gelin - Atelier de Biologie Chimie Informatique Structurale, Centre de Biologie Structurale, Univ Montpellier, CNRS, INSERM, 29 rue de Navacelles, 34090 Montpellier, France
Andrew Lemoff - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lauren G Zacharias - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
João S Patricio - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Thomas P Mathews - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Zhe Chen - Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Corinne Lionne - Atelier de Biologie Chimie Informatique Structurale, Centre de Biologie Structurale, Univ Montpellier, CNRS, INSERM, 29 rue de Navacelles, 34090 Montpellier, France
Gerta Hoxhaj - Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Gilles Labesse - Atelier de Biologie Chimie Informatique Structurale, Centre de Biologie Structurale, Univ Montpellier, CNRS, INSERM, 29 rue de Navacelles, 34090 Montpellier, France
Détails de publication: Science advances, Vol.11(4), p.eads2664
Note de subvention: S10 OD030312 / NIH HHS R01 GM143236 / NIGMS NIH HHS
Identifiants: 99136172809311
Unité académique: Centre de Biologie Structurale - CBS
Langue: English
Type de ressource: Journal article