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Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities

Barkauskaite, Eva; Brassington, Amy; Tan, Edwin S.; Warwicker, Jim; Dunstan, Mark S.; Banos, Benito; Lafite, Pierre; Ahel, Marijan; Mitchison, Timothy J.; Ahel, Ivan; Leys, David (2013) Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities. Nature Communications, 4 . 2164/1-2164/8. ISSN 2041-1723

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: glycosidase; poly(adenosine diphosphate ribose)
Subjects: NATURAL SCIENCES > Biology
Divisions: Division for Marine and Enviromental Research
Projects:
Project titleProject leaderProject codeProject type
Organski spojevi kao molekulski obilježivači antropogenog utjecaja na okoliš-Marijan Ahel098-0982934-2712MZOS
Depositing User: Marijan Ahel
Date Deposited: 28 Sep 2016 08:38
URI: http://fulir.irb.hr/id/eprint/3063
DOI: 10.1038/ncomms3164

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