Dataset Information

Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.

ABSTRACT: Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-acetyl-ADP-ribose (OAADPr) as a reaction product. The macrodomain is a ubiquitous protein module known to bind ADP-ribose derivatives, which diverged through evolution to support many different protein functions and pathways. The observation that some sirtuins and macrodomains are physically linked as fusion proteins or genetically coupled through the same operon, provided a clue that their functions might be connected. Indeed, here we demonstrate that the product of the sirtuin reaction OAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2, Escherichia coli YmdB, and the sirtuin-linked MacroD-like protein from Staphylococcus aureus. In addition, we show that the cell extracts derived from MacroD-deficient Neurospora crassa strain exhibit a major reduction in the ability to hydrolyze OAADPr. Our data support a novel function of macrodomains as OAADPr deacetylases and potential in vivo regulators of cellular OAADPr produced by NAD(+)-dependent deacetylation.

SUBMITTER: Chen D

PROVIDER: S-EPMC3075673 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.

Chen Dawei D Vollmar Melanie M Rossi Marianna N MN Phillips Claire C Kraehenbuehl Rolf R Slade Dea D Mehrotra Pawan V PV von Delft Frank F Crosthwaite Susan K SK Gileadi Opher O Denu John M JM Ahel Ivan I

The Journal of biological chemistry 20110121 15

Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-acetyl-ADP-ribose (OAADPr) as a reaction product. The macrodomain is a ubiquitous protein module known to bind ADP-ribose derivatives, which diverged through evolution to support many different protein functions and pathways. The observation that some sirtuins and macrodomains are physically linked as fusi ...[more]

PMID: 21257746

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Project description:Sirtuins catalyze the NAD(+)-dependent deacetylation of target proteins, which are regulated by this reversible lysine modification. During deacetylation, the glycosidic bond of the nicotinamide ribose is cleaved to yield nicotinamide and the ribose accepts the acetyl group from substrate to produce O-acetyl-ADP-ribose (OAADPr), which exists as an approximately 50:50 mixture of 2' and 3' isomers at neutral pH. Discovery of this metabolite has fueled the idea that OAADPr may play an important role in the biology associated with sirtuins, acting as a signaling molecule and/or an important substrate for downstream enzymatic processes. Evidence for OAADPr-metabolizing enzymes indicates that at least three distinct activities exist that could modulate the cellular levels of this NAD(+)-derived metabolite. In Saccharomyces cerevisiae, NUDIX hydrolase Ysa1 cleaves OAADPr to AMP and 2- and 3-O-acetylribose-5-phosphate, lowering the cellular levels of OAADPr. A buildup of OAADPr and ADPr has been linked to a metabolic shift that lowers endogenous reactive oxygen species and diverts glucose towards preventing oxidative damage. In vitro, the mammalian enzyme ARH3 hydrolyzes OAADPr to acetate and ADPr. A third nuclear-localized activity appears to utilize OAADPr to transfer the acetyl-group to another small molecule, whose identity remains unknown. Recent studies suggest that OAADPr may regulate gene silencing by facilitating the assembly and loading of the Sir2-4 silencing complex onto nucleosomes. In mammalian cells, the Trpm2 cation channel is gated by both OAADPr and ADP-ribose. Binding is mediated by the NUDIX homology (NudT9H) domain found within the intracellular portion of the channel. OAADPr is capable of binding the Macro domain of splice variants from histone protein MacroH2A, which is highly enriched at heterochromatic regions. With recently developed tools, the pace of new discoveries of OAADPr-dependent processes should facilitate new molecular insight into the diverse biological processes modulated by sirtuins.

Dataset Information

Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.

Publications

Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.

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