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

被引：125

作者：

Barkauskaite, Eva ^{[1
]}

Brassington, Amy ^{[2
]}

Tan, Edwin S. ^{[3
]}

Warwicker, Jim ^{[2
]}

Dunstan, Mark S. ^{[2
]}

Banos, Benito ^{[1
]}

Lafite, Pierre ^{[4
]}

Ahel, Marijan ^{[5
]}

Mitchison, Timothy J. ^{[3
]}

Ahel, Ivan ^{[1
,6
]}

Leys, David ^{[2
]}

机构：

[1] Univ Manchester, Paterson Inst Canc Res, Canc Res UK, Manchester M20 4BX, Lancs, England

[2] Univ Manchester, Manchester Inst Biotechnol, Manchester M1 7DN, Lancs, England

[3] Harvard Univ, Sch Med, Boston, MA 02115 USA

[4] Univ Orleans, CNRS UMR 7311, Inst Chim Organ & Analyt, F-45067 Orleans 2, France

[5] Rudjer Boskovic Inst, Zagreb 10000, Croatia

[6] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

来源：

NATURE COMMUNICATIONS | 2013年 / 4卷

基金：

欧洲研究理事会; 英国生物技术与生命科学研究理事会; 美国国家卫生研究院;

关键词：

PROTEINS; BINDING; PURIFICATION; MECHANISM;

D O I：

10.1038/ncomms3164

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：8

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