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Journal Article

Electron microscopy structure of human APC/C-CDH1-EMI1 reveals multimodal mechanism of E3 ligase shutdown.

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

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Fulltext (public)

1819434.pdf
(Publisher version), 3MB

Supplementary Material (public)

1819434_Supplement_1.pdf
(Supplementary material), 8MB

Citation

Frye, J., Brown, N. G., Petzold, G., Watson, E. R., Grace, C. R. R., Nourse, A., et al. (2013). Electron microscopy structure of human APC/C-CDH1-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nature Structural and Molecular Biology, 20(7), 827-835. doi:10.1038/nsmb.2593.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-1732-8
Abstract
The anaphase-promoting complex/cyclosome (APC/C) is a similar to 1.5-MDa multiprotein E3 ligase enzyme that regulates cell division by promoting timely ubiquitin-mediated proteolysis of key cell-cycle regulatory proteins. Inhibition of human APC/C-CDH1 during interphase by early mitotic inhibitor 1 (EMI1) is essential for accurate coordination of DNA synthesis and mitosis. Here, we report a hybrid structural approach involving NMR, electron microscopy and enzymology, which reveal that EMI1's 143-residue C-terminal domain inhibits multiple APC/C-CDH1 functions. The intrinsically disordered D-box, linker and tail elements, together with a structured zinc-binding domain, bind distinct regions of APC/C-CDH1 to synergistically both block the substrate-binding site and inhibit ubiquitin-chain elongation. The functional importance of intrinsic structural disorder is explained by enabling a small inhibitory domain to bind multiple sites to shut down various functions of a 'molecular machine' nearly 100 times its size.