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

Author

Listed:
  • Johannes Gregor Matthias Rack

    (University of Oxford)

  • Qiang Liu

    (Leiden University, Leiden Institute of Chemistry)

  • Valentina Zorzini

    (University of Oxford)

  • Jim Voorneveld

    (Leiden University, Leiden Institute of Chemistry)

  • Antonio Ariza

    (University of Oxford)

  • Kourosh Honarmand Ebrahimi

    (University of Oxford, Chemistry Research Laboratory)

  • Julia M. Reber

    (University of Konstanz)

  • Sarah C. Krassnig

    (University of Konstanz)

  • Dragana Ahel

    (University of Oxford)

  • Gijsbert A. Marel

    (Leiden University, Leiden Institute of Chemistry)

  • Aswin Mangerich

    (University of Konstanz)

  • James S. O. McCullagh

    (University of Oxford, Chemistry Research Laboratory)

  • Dmitri V. Filippov

    (Leiden University, Leiden Institute of Chemistry)

  • Ivan Ahel

    (University of Oxford)

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.

Suggested Citation

  • Johannes Gregor Matthias Rack & Qiang Liu & Valentina Zorzini & Jim Voorneveld & Antonio Ariza & Kourosh Honarmand Ebrahimi & Julia M. Reber & Sarah C. Krassnig & Dragana Ahel & Gijsbert A. Marel & As, 2021. "Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24723-3
    DOI: 10.1038/s41467-021-24723-3
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