Crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation.

Autor:	Mary C; Atelier de Biologie Chimie Informatique Structurale, CNRS, INSERM, Univ Montpellier, Centre de Biologie Structurale, Montpellier, France., Soflaee MH; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Kesavan R; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Gelin M; Atelier de Biologie Chimie Informatique Structurale, CNRS, INSERM, Univ Montpellier, Centre de Biologie Structurale, Montpellier, France., Brown H; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Zacharias G; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Mathews TP; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Lemoff A; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Lionne C; Atelier de Biologie Chimie Informatique Structurale, CNRS, INSERM, Univ Montpellier, Centre de Biologie Structurale, Montpellier, France., Labesse G; Atelier de Biologie Chimie Informatique Structurale, CNRS, INSERM, Univ Montpellier, Centre de Biologie Structurale, Montpellier, France. Electronic address: labesse@cbs.cnrs.fr., Hoxhaj G; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: gerta.hoxhaj@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2022 Sep 01; Vol. 82 (17), pp. 3299-3311.e8. Date of Electronic Publication: 2022 Jul 21.
DOI:	10.1016/j.molcel.2022.06.026
Abstrakt:	NAD + kinases (NADKs) are metabolite kinases that phosphorylate NAD + molecules to make NADP + , a limiting substrate for the generation of reducing power NADPH. NADK2 sustains mitochondrial NADPH production that enables proline biosynthesis and antioxidant defense. However, its molecular architecture and mechanistic regulation remain undescribed. Here, we report the crystal structure of human NADK2, revealing a substrate-driven mode of activation. We find that NADK2 presents an unexpected dimeric organization instead of the typical tetrameric assemblage observed for other NADKs. A specific extended segment (aa 325-365) is crucial for NADK2 dimerization and activity. Moreover, we characterize numerous acetylation events, including those on Lys76 and Lys304, which reside near the active site and inhibit NADK2 activity without disrupting dimerization, thereby reducing mitochondrial NADP(H) production, proline synthesis, and cell growth. These findings reveal important molecular insight into the structure and regulation of a vital enzyme in mitochondrial NADPH and proline metabolism. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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