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TitleElectron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
Journal, issue, pagesNat Struct Mol Biol, Vol. 20, Issue 7, Page 827-835, Year 2013
Publish dateMay 26, 2013
AuthorsJeremiah J Frye / Nicholas G Brown / Georg Petzold / Edmond R Watson / Christy R R Grace / Amanda Nourse / Marc A Jarvis / Richard W Kriwacki / Jan-Michael Peters / Holger Stark / Brenda A Schulman /
PubMed AbstractThe 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 ...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.
External linksNat Struct Mol Biol / PubMed:23708605 / PubMed Central
MethodsEM (single particle) / NMR (solution)
Resolution20.0 - 25.0 Å
Structure data

EMDB-2353:
Anaphase Promoting Complex with an Emi1 deletion mutant bound
Method: EM (single particle) / Resolution: 25.0 Å

EMDB-2354:
Anaphase Promoting Complex with full length Emi1 bound
Method: EM (single particle) / Resolution: 20.0 Å

PDB-2m6n:
3D solution structure of EMI1 (Early Mitotic Inhibitor 1)
Method: SOLUTION NMR

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / EMI1 / APC / E3 ligase / ZBR

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