Journal
MOLECULAR CELL
Volume 39, Issue 5, Pages 784-796Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2010.08.030
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Funding
- ALSAC
- St. Jude Cancer Center
- National Institutes of Health (NIH) [R01GM069530, R01CA082491]
- ERC
- Howard Hughes Medical Institute
- NIH NCRR [RR-15301]
- US DOE [W-31-109-Eng-38]
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In ubiquitin-like protein (UBL) cascades, a thioester-linked E2 similar to UBL complex typically interacts with an E3 enzyme for UBL transfer to the target. Here we demonstrate a variant mechanism, whereby the E2 Ubc12 functions with two E3s, Hrt1 and Dcn1, for ligation of the UBL Rub1 to Cdc53's WHB subdomain. Hrt1 functions like a conventional RING E3, with its N terminus recruiting Cdc53 and C-terminal RING activating Ubc12 Rub1. Dcn1's potentiating neddylation domain (Dcn1(P)) acts as an additional E3, reducing nonspecific Hrt1-mediated Ubc12 similar to Rub1 discharge and directing Ubc12's active site to Cdc53. Crystal structures of Dcn1(P)-Cdc53(WHB) and Ubc12 allow modeling of a catalytic complex, supported by mutational data. We propose that Dcn1's interactions with both Cdc53 and Ubc12 would restrict the otherwise flexible Hill RING-bound Ubc12 Rub1 to a catalytically competent orientation. Our data reveal mechanisms by which two E3s function synergistically to promote UBL transfer from one E2 to a target.
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