Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases.
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.
Department of Biomolecular Chemistry and Wisconsin Institute for Discovery, University of Wisconsin, Madison, Wisconsin 53706, USA.
Dawei
D
Chen
Melanie
M
Vollmar
Marianna N
MN
Rossi
Claire
C
Phillips
Rolf
R
Kraehenbuehl
Dea
D
Slade
Pawan V
PV
Mehrotra
Frank
F
von Delft
Susan K
SK
Crosthwaite
Opher
O
Gileadi
John M
JM
Denu
Ivan
I
Ahel
D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009492:Neurospora crassa / Q000201:enzymology* / Q000235:genetics; D017434:Protein Structure, Tertiary; D037761:Sirtuins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics
D029968:Escherichia coli Proteins; D005656:Fungal Proteins; D037761:Sirtuins
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