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- Title
Electron microscopy structure of human APC/C<sup>CDH1</sup>-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
- Authors
Frye, Jeremiah J; Brown, Nicholas G; Petzold, Georg; Watson, Edmond R; Grace, Christy R R; Nourse, Amanda; Jarvis, Marc A; Kriwacki, Richard W; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A
- Abstract
The anaphase-promoting complex/cyclosome (APC/C) is a ~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/CCDH1 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/CCDH1 functions. The intrinsically disordered D-box, linker and tail elements, together with a structured zinc-binding domain, bind distinct regions of APC/CCDH1 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.
- Subjects
ELECTRON microscopy; COMBINED modality therapy; CELL division; NUCLEIC acids; ENZYMES
- Publication
Nature Structural & Molecular Biology, 2013, Vol 20, Issue 7, p827
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2593