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Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases

DOI: 10.1126/sciadv.abc0418 DOI Help

Authors: Chatrin Chatrin (Cancer Research UK Beatson Institute; University of Glasgow) , Mads Gabrielsen (Cancer Research UK Beatson Institute) , Lori Buetow (Cancer Research UK Beatson Institute) , Mark A. Nakasone (Cancer Research UK Beatson Institute) , Syed F. Ahmed (Cancer Research UK Beatson Institute) , David Sumpton (Cancer Research UK Beatson Institute) , Gary J. Sibbet (Cancer Research UK Beatson Institute) , Brian O. Smith (University of Glasgow) , Danny Huang (Cancer Research UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 16258

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Documents:
eabc0418.full.pdf