da Fonsceca, P.C.A. and Kong, E.H. and Zhang, Z. and Schreiber, A. and Williams, Mark A. and Morris, E.P. and Barford, D. (2011) Structures of APC/C-CDH1 with substrates identify Cdh1 and Apc10 as the D-box co-receptor. Nature 470 , pp. 274-278. ISSN 0028-0836.
Abstract
The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box and KEN (Lys-Glu-Asn)-box. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits the structural basis for substrate recognition and ubiquitylation is not understood. Here we investigate budding yeast APC/C using single-particle electron microscopy and determine a cryo-electron microscopy map of APC/C in complex with the Cdh1 co-activator protein (APC/CCdh1) bound to a D-box peptide at ~10 Å resolution. We find that a combined catalytic and substrate-recognition module is located within the central cavity of the APC/C assembled from Cdh1, Apc10—a core APC/C subunit previously implicated in substrate recognition and the cullin domain of Apc2. Cdh1 and Apc10, identified from difference maps, create a co-receptor for the D-box following repositioning of Cdh1 towards Apc10. Using NMR spectroscopy we demonstrate specific D-box–Apc10 interactions, consistent with a role for Apc10 in directly contributing towards D-box recognition by the APC/CCdh1 complex. Our results rationalize the contribution of both co-activator and core APC/C subunits to D-box recognition and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.
Metadata
| Item Type: | Article |
|---|---|
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Bioinformatics, Bloomsbury Centre for (Closed), Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Mark Williams |
| Date Deposited: | 15 Nov 2012 13:47 |
| Last Modified: | 02 Aug 2023 17:00 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/5659 |
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