Download MendeleyElectron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
Frye, J.J., Brown, N.G., Petzold, G., Watson, E.R., Grace, C.R., Nourse, A., Jarvis, M.A., Kriwacki, R.W., Peters, J.M., Stark, H., Schulman, B.A.(2013) Nat Struct Mol Biol 20: 827-835
- PubMed: 23708605
- DOI: https://doi.org/10.1038/nsmb.2593
- Primary Citation of Related Structures:
2M6N - PubMed 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/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.
Organizational Affiliation:
1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
