Electron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown.
Nat Struct Mol Biol
; 20(7): 827-35, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23708605
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Caderinas
/
Proteínas de Ciclo Celular
/
Complexos Ubiquitina-Proteína Ligase
/
Proteínas F-Box
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article