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Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector

Author

Listed:
  • Anil Akturk

    (Cornell University)

  • David J. Wasilko

    (Cornell University)

  • Xiaochun Wu

    (Cornell University)

  • Yao Liu

    (Purdue University)

  • Yong Zhang

    (Purdue University)

  • Jiazhang Qiu

    (Purdue University)

  • Zhao-Qing Luo

    (Purdue University)

  • Katherine H. Reiter

    (University of Washington)

  • Peter S. Brzovic

    (University of Washington)

  • Rachel E. Klevit

    (University of Washington)

  • Yuxin Mao

    (Cornell University)

Abstract

Ubiquitination is a post-translational modification that regulates many cellular processes in eukaryotes1–4. The conventional ubiquitination cascade culminates in a covalent linkage between the C terminus of ubiquitin (Ub) and a target protein, usually on a lysine side chain1,5. Recent studies of the Legionella pneumophila SidE family of effector proteins revealed a ubiquitination method in which a phosphoribosyl ubiquitin (PR-Ub) is conjugated to a serine residue on substrates via a phosphodiester bond6–8. Here we present the crystal structure of a fragment of the SidE family member SdeA that retains ubiquitination activity, and determine the mechanism of this unique post-translational modification. The structure reveals that the catalytic module contains two distinct functional units: a phosphodiesterase domain and a mono-ADP-ribosyltransferase domain. Biochemical analysis shows that the mono-ADP-ribosyltransferase domain-mediated conversion of Ub to ADP-ribosylated Ub (ADPR-Ub) and the phosphodiesterase domain-mediated ligation of PR-Ub to substrates are two independent activities of SdeA. Furthermore, we present two crystal structures of a homologous phosphodiesterase domain from the SidE family member SdeD 9 in complexes with Ub and ADPR-Ub. The structures suggest a mechanism for how SdeA processes ADPR-Ub to PR-Ub and AMP, and conjugates PR-Ub to a serine residue in substrates. Our study establishes the molecular mechanism of phosphoribosyl-linked ubiquitination and will enable future studies of this unusual type of ubiquitination in eukaryotes.

Suggested Citation

  • Anil Akturk & David J. Wasilko & Xiaochun Wu & Yao Liu & Yong Zhang & Jiazhang Qiu & Zhao-Qing Luo & Katherine H. Reiter & Peter S. Brzovic & Rachel E. Klevit & Yuxin Mao, 2018. "Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector," Nature, Nature, vol. 557(7707), pages 729-733, May.
    • Handle: RePEc:nat:nature:v:557:y:2018:i:7707:d:10.1038_s41586-018-0147-6
    DOI: 10.1038/s41586-018-0147-6
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    Cited by:

    1. Zhengrui Zhang & Jiaqi Fu & Johannes Gregor Matthias Rack & Chuang Li & Jim Voorneveld & Dmitri V. Filippov & Ivan Ahel & Zhao-Qing Luo & Chittaranjan Das, 2024. "Legionella metaeffector MavL reverses ubiquitin ADP-ribosylation via a conserved arginine-specific macrodomain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Michael Adams & Rahul Sharma & Thomas Colby & Felix Weis & Ivan Matic & Sagar Bhogaraju, 2021. "Structural basis for protein glutamylation by the Legionella pseudokinase SidJ," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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