Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo- glycohydrolase activities (CROSBI ID 201880)
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Podaci o odgovornosti
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
engleski
Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo- glycohydrolase activities
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.
glycosidase; poly(adenosine diphosphate ribose)
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