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Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal

DOI: 10.1038/s41467-021-24723-3 DOI Help

Authors: Johannes Gregor Matthias Rack (University of Oxford) , Qiang Liu (Leiden University) , Valentina Zorzini (University of Oxford) , Jim Voorneveld (Leiden University) , Antonio Ariza (University of Leeds) , Kourosh Honarmand Ebrahimi (University of Oxford) , Julia M. Reber (University of Konstanz) , Sarah C. Krassnig (University of Konstanz) , Dragana Ahel (University of Oxford) , Gijsbert A. Van Der Marel (Leiden University) , Aswin Mangerich (University of Konstanz) , James S. O. Mccullagh (University of Oxford) , Dmitri V. Filippov (Leiden University) , Ivan Ahel (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 18069 , 23459

Open Access Open Access

Abstract: Poly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry.

Journal Keywords: Chemical tools; Enzyme mechanisms; PolyADP-ribosylation

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 30/07/2021 19:34


Discipline Tags:

Catalysis Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)