Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases (original) (raw)

Chatrin, Chatrin, Gabrielsen, Mads ORCID: https://orcid.org/0000-0002-9848-2276, Buetow, Lori, Nakasone, Mark A., Ahmed, Syed F., Sumpton, David, Sibbet, Gary J., Smith, Brian O. ORCID: https://orcid.org/0000-0003-3363-4168 and Huang, Danny T. ORCID: https://orcid.org/0000-0002-6192-259X(2020) Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases.Science Advances, 6(38), eabc0418. (doi: 10.1126/sciadv.abc0418) (PMID:32948590) (PMCID:PMC7500938)

Abstract

Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitin’s Gly76. Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+. Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future studies directed at understanding the increasingly complex network of ubiquitin cross-talk.

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