RT Journal Article
SR Electronic
T1 Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabc0418
DO 10.1126/sciadv.abc0418
VO 6
IS 38
A1 Chatrin, Chatrin
A1 Gabrielsen, Mads
A1 Buetow, Lori
A1 Nakasone, Mark A.
A1 Ahmed, Syed F.
A1 Sumpton, David
A1 Sibbet, Gary J.
A1 Smith, Brian O.
A1 Huang, Danny T.
YR 2020
UL http://advances.sciencemag.org/content/6/38/eabc0418.abstract
AB 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.