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

Chatrin, C., Gabrielsen, M. , Buetow, L., Nakasone, M. A., Ahmed, S. F., Sumpton, D., Sibbet, G. J., Smith, B. O. and Huang, D. T. (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)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sumpton, Mr David and Chatrin, Chatrin and Huang, Professor Danny and Gabrielsen, Dr Mads and Sibbet, Dr Gary and Smith, Dr Brian and Buetow, Dr Lori
Authors: Chatrin, C., Gabrielsen, M., Buetow, L., Nakasone, M. A., Ahmed, S. F., Sumpton, D., Sibbet, G. J., Smith, B. O., and Huang, D. T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Science Advances 6(38):eabc0418
Publisher Policy:Reproduced under a Creative Commons licence

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