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

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.

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 Creators:
Frye, J., Author
Brown, N. G., Author
Petzold, G., Author
Watson, E. R., Author
Grace, C. R. R., Author
Nourse, A., Author
Jarvis, M. A., Author
Kriwacki, R. W., Author
Peters, J. M., Author
Stark, H.1, Author           
Schulman, B. A., Author
Affiliations:
1Research Group of 3D Electron Cryo-Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578577              

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 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.

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Language(s): eng - English
 Dates: 2013-05-262013-07
 Publication Status: Issued
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/nsmb.2593
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Title: Nature Structural and Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 20 (7) Sequence Number: - Start / End Page: 827 - 835 Identifier: -