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Journal Article

Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly.

MPS-Authors
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Dube,  P.
Research Group of 3D Electron Cryo-Microscopy, MPI for biophysical chemistry, Max Planck Society;

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Stark,  H.
Research Group of 3D Electron Cryo-Microscopy, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2077050.pdf
(Publisher version), 5MB

Supplementary Material (public)

2077050_Suppl_1.pdf
(Supplementary material), 9MB

2077050_Suppl_2.pdf
(Supplementary material), 14MB

Citation

Brown, N. G., Watson, E. R., Weissmann, F., Jarvis, M. A., VanderLinden, R., Grace, C., et al. (2014). Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly. Molecular Cell, 56(2), 246-260. doi:10.1016/j.molcel.2014.09.009.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-4AB1-9
Abstract
Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RINGE3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here we show that human APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation.