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

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2021
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Rack, Johannes Gregor Matthias
Liu, Qiang
Zorzini, Valentina
Voorneveld, Jim
Ariza, Antonio
Filippov, Dmitri V.
Ahel, Ivan
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Nature Communications. Nature Publishing Group. 2021, 12(1), 4581. eISSN 2041-1723. Available under: doi: 10.1038/s41467-021-24723-3
Zusammenfassung

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.

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ISO 690RACK, Johannes Gregor Matthias, Qiang LIU, Valentina ZORZINI, Jim VOORNEVELD, Antonio ARIZA, Julia M. REBER, Sarah C. KRASSNIG, Aswin MANGERICH, Dmitri V. FILIPPOV, Ivan AHEL, 2021. Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal. In: Nature Communications. Nature Publishing Group. 2021, 12(1), 4581. eISSN 2041-1723. Available under: doi: 10.1038/s41467-021-24723-3
BibTex
@article{Rack2021-12Mecha-54457,
  year={2021},
  doi={10.1038/s41467-021-24723-3},
  title={Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal},
  number={1},
  volume={12},
  journal={Nature Communications},
  author={Rack, Johannes Gregor Matthias and Liu, Qiang and Zorzini, Valentina and Voorneveld, Jim and Ariza, Antonio and Reber, Julia M. and Krassnig, Sarah C. and Mangerich, Aswin and Filippov, Dmitri V. and Ahel, Ivan},
  note={Article Number: 4581}
}
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