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Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex

Nature Cell Biology volume 15, pages 797806 (2013) | Download Citation


The anaphase-promoting complex (APC) is the crucial ubiquitin ligase targeting the regulatory machinery of the cell cycle. Emi1, a major modulator of APC activity, is thought to act competitively as a pseudosubstrate. We show that the modulation of APC activity is more subtle: Emi1 inhibits ubiquitylation at both substrate binding and separately at the step of ubiquitin transfer to APC-bound substrates. The zinc-binding region of Emi1 allows multiple monoubiquitylation of substrates, but preferentially suppresses the ubiquitin chain elongation by UBCH10. Furthermore, the carboxy-terminal tail of Emi1 antagonizes chain elongation by Ube2S, by competitively preventing its binding to the APC cullin subunit through electrostatic interaction. Combinatorially, Emi1 effectively stabilizes APC substrates by suppressing ubiquitin chain extension. Deubiquitylating enzymes can then convert inhibited substrates to their basal state. Chain elongation may be a particularly sensitive step for controlling degradation, and this study provides the first kinetic evidence for how it is inhibited.

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We wish to thank the members of the Kirschner Laboratory for advice, especially T. Wu and Y. Lu for discussions and insightful suggestions. The work was supported by a grant from the National Institute of General Medical Sciences, R01 GM039023.

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  1. Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA

    • Weiping Wang
    •  & Marc W. Kirschner


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W.W. and M.W.K planned the project. W.W. designed, carried out and analysed all experiments. W.W. and M.W.K. interpreted the data. The manuscript was written by W.W. and M.W.K.

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The authors declare no competing financial interests.

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Correspondence to Marc W. Kirschner.

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