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The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase

DOI: 10.1038/nature10404 DOI Help
PMID: 21892188 PMID Help

Authors: Dea Slade (University of Manchester) , Mark S. Dunstan (Manchester Interdisciplinary Biocentre) , Eva Barkauskaite (University of Manchester) , Ria Weston (University of Manchester) , Pierre Lafite (University of Manchester) , Neil Dixon (Manchester Interdisciplinary Biocentre) , Marijan Ahel (Rudjer Boskovic Institute) , David Leys (University of Manchester) , Ivan Ahel (University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 477 , PAGES 616 - 620

State: Published (Approved)
Published: September 2011

Open Access Open Access

Abstract: Post-translational modification of proteins by poly(ADP-ribosyl)ation regulates many cellular pathways that are critical for genome stability, including DNA repair, chromatin structure, mitosis and apoptosis1. Poly(ADP-ribose) (PAR) is composed of repeating ADP-ribose units linked via a unique glycosidic ribose–ribose bond, and is synthesized from NAD by PAR polymerases1, 2. PAR glycohydrolase (PARG) is the only protein capable of specific hydrolysis of the ribose–ribose bonds present in PAR chains; its deficiency leads to cell death3, 4. Here we show that filamentous fungi and a number of bacteria possess a divergent form of PARG that has all the main characteristics of the human PARG enzyme. We present the first PARG crystal structure (derived from the bacterium Thermomonospora curvata), which reveals that the PARG catalytic domain is a distant member of the ubiquitous ADP-ribose-binding macrodomain family5, 6. High-resolution structures of T. curvata PARG in complexes with ADP-ribose and the PARG inhibitor ADP-HPD, complemented by biochemical studies, allow us to propose a model for PAR binding and catalysis by PARG. The insights into the PARG structure and catalytic mechanism should greatly improve our understanding of how PARG activity controls reversible protein poly(ADP-ribosyl)ation and potentially of how the defects in this regulation are linked to human disease.

Journal Keywords: Adenosine; Amino; Biocatalysis; Catalytic; Crystallography; X-Ray; Evolution; Molecular; Glycoside; Humans; Hydrolysis; Models; Molecular; Phylogeny; Poly; Poly(ADP-ribose); Protein; Proteins; Pyrrolidines

Subject Areas: Medicine, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

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