| Structural highlights
Function
[FBX5_HUMAN] Regulates progression through early mitosis by inhibiting the anaphase promoting complex/cyclosome (APC). Binds to the APC activators CDC20 and FZR1/CDH1 to prevent APC activation. Can also bind directly to the APC to inhibit substrate-binding.[1] [2]
Publication Abstract from PubMed
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.
Electron microscopy structure of human APC/C-EMI1 reveals multimodal mechanism of E3 ligase shutdown.,Frye JJ, Brown NG, Petzold G, Watson ER, Grace CR, Nourse A, Jarvis MA, Kriwacki RW, Peters JM, Stark H, Schulman BA Nat Struct Mol Biol. 2013 May 26. doi: 10.1038/nsmb.2593. PMID:23708605[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol. 2002 May;4(5):358-66. PMID:11988738 doi:10.1038/ncb785
- ↑ Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL, Loktev A, Jackson PK. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006 Sep 1;20(17):2410-20. Epub 2006 Aug 18. PMID:16921029 doi:gad.1454006
- ↑ Frye JJ, Brown NG, Petzold G, Watson ER, Grace CR, Nourse A, Jarvis MA, Kriwacki RW, Peters JM, Stark H, Schulman BA. Electron microscopy structure of human APC/C-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nat Struct Mol Biol. 2013 May 26. doi: 10.1038/nsmb.2593. PMID:23708605 doi:10.1038/nsmb.2593
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