Reference: Scott DC, et al. (2010) A dual E3 mechanism for Rub1 ligation to Cdc53. Mol Cell 39(5):784-96

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Abstract


In ubiquitin-like protein (UBL) cascades, a thioester-linked E2 approximately 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 approximately Rub1. Dcn1's "potentiating neddylation" domain (Dcn1(P)) acts as an additional E3, reducing nonspecific Hrt1-mediated Ubc12 approximately 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 Hrt1 RING-bound Ubc12 approximately 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.CI - Copyright (c) 2010 Elsevier Inc. All rights reserved.

Reference Type
Journal Article | Research Support, Non-U.S. Gov't | Research Support, N.I.H., Extramural | Research Support, U.S. Gov't, Non-P.H.S.
Authors
Scott DC, Monda JK, Grace CR, Duda DM, Kriwacki RW, Kurz T, Schulman BA
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