title: Isoform-specific targeting and interaction domains in human nicotinamide mononucleotide adenylyltransferases.
abstract: Several important signaling pathways require NAD as substrate, thereby leading to significant consumption of the molecule. Because NAD is also an essential redox carrier, its continuous resynthesis is vital. In higher eukaryotes, maintenance of compartmentalized NAD pools is critical, but so far rather little is known about the regulation and subcellular distribution of NAD biosynthetic enzymes. The key step in NAD biosynthesis is the formation of the dinucleotide by nicotinamide/nicotinic acid mononucleotide adenylyltransferases (NMNATs). The three human isoforms were localized to the nucleus, the Golgi complex, and mitochondria. Here, we show that their genes contain unique exons that encode isoform-specific domains to mediate subcellular targeting and post-translational modifications. These domains are dispensable for catalytic activity, consistent with their absence from NMNATs of lower organisms. We further demonstrate that the Golgi-associated NMNAT is palmitoylated at two adjacent cysteine residues of its isoform-specific domain and thereby anchored at the cytoplasmic surface, a potential mechanism to regulate the cytosolic NAD pool. Insertion of unique domains thus provides a yet unrecognized enzyme targeting mode, which has also been adapted to modulate subcellular NAD supply.
authors.affiliation: Department of Molecular Biology, University of Bergen, N-5008 Bergen, Norway.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lau
authors.forename: Christian
authors.initials: C
authors.lastname: Dölle
authors.forename: Toni I
authors.initials: TI
authors.lastname: Gossmann
authors.forename: Line
authors.initials: L
authors.lastname: Agledal
authors.forename: Marc
authors.initials: M
authors.lastname: Niere
authors.forename: Mathias
authors.initials: M
authors.lastname: Ziegler
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D004734:Energy Metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000737:chemistry*; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020033:Protein Isoforms; D011506:Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D003545:Cysteine
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