Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases

TitleMacrodomain-containing proteins are new mono-ADP-ribosylhydrolases
Publication TypeJournal Article
Year of Publication2013
AuthorsRosenthal F., Feijs K.LH, Frugier E., Bonalli M., Forst A.H, Imhof R., Winkler H.C, Fischer D., Caflisch A., Hassa P.O, Lüscher B., Hottiger M.O
JournalNature Structural & Molecular Biology
Volume20
Issue4
Pagination502-507
Date Published2013 Apr
Type of ArticleResearch Article
ISSN1545-9985
KeywordsAdenosine Diphosphate Ribose, Humans, Models, Molecular, Mutagenesis, N-Glycosyl Hydrolases
Abstract

ADP-ribosylation is an important post-translational protein modification (PTM) that regulates diverse biological processes. ADP-ribosyltransferase diphtheria toxin-like 10 (ARTD10, also known as PARP10) mono-ADP-ribosylates acidic side chains and is one of eighteen ADP-ribosyltransferases that catalyze mono- or poly-ADP-ribosylation of target proteins. Currently, no enzyme is known that reverses ARTD10-catalyzed mono-ADP-ribosylation. Here we report that ARTD10-modified targets are substrates for the macrodomain proteins MacroD1, MacroD2 and C6orf130 from Homo sapiens as well as for the macrodomain protein Af1521 from archaebacteria. Structural modeling and mutagenesis of MacroD1 and MacroD2 revealed a common core structure with Asp102 and His106 of MacroD2 implicated in the hydrolytic reaction. Notably, MacroD2 reversed the ARTD10-catalyzed, mono-ADP-ribose-mediated inhibition of glycogen synthase kinase 3β (GSK3β) in vitro and in cells, thus underlining the physiological and regulatory importance of mono-ADP-ribosylhydrolase activity. Our results establish macrodomain-containing proteins as mono-ADP-ribosylhydrolases and define a class of enzymes that renders mono-ADP-ribosylation a reversible modification.

DOI10.1038/nsmb.2521
pubindex

0171

Alternate JournalNat. Struct. Mol. Biol.
PubMed ID23474714
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