Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities.
Authors
Barkauskaite, EvaBrassington, A
Tan, E
Warwicker, J
Dunstan, M
Banos, Benito
Lafite, P
Ahel, M
Mitchison, T
Ahel, Ivan
Leys, D
Affiliation
Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.Issue Date
2013-08-06
Metadata
Show full item recordAbstract
Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer is catalysed by poly(ADP-ribose) glycohydrolase (PARG), whose endo-glycohydrolase activity generates PAR fragments. Here we present the crystal structure of PARG incorporating the PAR substrate. The two terminal ADP-ribose units of the polymeric substrate are bound in exo-mode. Biochemical and modelling studies reveal that PARG acts predominantly as an exo-glycohydrolase. This preference is linked to Phe902 (human numbering), which is responsible for low-affinity binding of the substrate in endo-mode. Our data reveal the mechanism of poly-ADP-ribosylation reversal, with ADP-ribose as the dominant product, and suggest that the release of apoptotic PAR fragments occurs at unusual PAR/PARG ratios.Citation
Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities. 2013, 4:2164 Nat CommunJournal
Nature CommunicationsDOI
10.1038/ncomms3164PubMed ID
23917065Type
ArticleLanguage
enISSN
2041-1723ae974a485f413a2113503eed53cd6c53
10.1038/ncomms3164