Structure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria.

TitleStructure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria.
Publication TypeJournal Article
Year of Publication2022
AuthorsDu, J, Estrella, M, Solorio-Kirpichyan, K, Jeffrey, PD, Korennykh, A
JournalProc Natl Acad Sci U S A
Volume119
Issue26
Paginatione2200923119
Date Published2022 06 28
ISSN1091-6490
KeywordsAnimals, Humans, Mitochondria, Mitochondrial Proteins, NAD, NADP, Phosphotransferases (Alcohol Group Acceptor), Protein Multimerization
Abstract

<p>All kingdoms of life produce essential nicotinamide dinucleotide NADP(H) using NAD kinases (NADKs). A panel of published NADK structures from bacteria, eukaryotic cytosol, and yeast mitochondria revealed similar tetrameric enzymes. Here, we present the 2.8-Å structure of the human mitochondrial kinase NADK2 with a bound substrate, which is an exception to this uniformity, diverging both structurally and biochemically from NADKs. We show that NADK2 harbors a unique tetramer disruptor/dimerization lement, which is conserved in itochondrial inases of nimals (EMKA) and absent from other NADKs. EMKA stabilizes the NADK2 dimer but prevents further NADK2 oligomerization by blocking the tetramerization interface. This structural change bears functional consequences and alters the activation mechanism of the enzyme. Whereas tetrameric NADKs undergo cooperative activation via oligomerization, NADK2 is a constitutively active noncooperative dimer. Thus, our data point to a unique regulation of NADP(H) synthesis in animal mitochondria achieved via structural adaptation of the NADK2 kinase.</p>

DOI10.1073/pnas.2200923119
Alternate JournalProc Natl Acad Sci U S A
PubMed ID35733246
PubMed Central IDPMC9245612
Grant ListP30 GM133893 / GM / NIGMS NIH HHS / United States
R01 GM110161 / GM / NIGMS NIH HHS / United States