Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector

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 and Yuxin Mao ()
Additional contact information
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

Nature, 2018, vol. 557, issue 7707, 729-733

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41586-018-0147-6

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