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Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor

DOI: 10.1038/nature09625 DOI Help
PMID: 21107322 PMID Help

Authors: David Barford (Institute of Cancer Research) , A Schreiber (Institute of Chemistry and Biochemistry, Free University Berlin) , Paula C. A. Da Fonseca (Institute of Cancer Research) , Eric Kong (Institute of Cancer Research) , Ziguo Zhang (Institute of Cancer Research) , Mark A. Williams (Birkbeck University of London) , Edward P. Morris (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 470 (7333) , PAGES 274-278

State: Published (Approved)
Published: February 2011
Diamond Proposal Number(s): 6385

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 mitosis1, 2. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box3 and KEN (Lys-Glu-Asn)-box4. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits1, 2, 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 recognition5, 6, 7—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 recognition8, 9 and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.

Journal Keywords: Structural Biology; Biochemestry

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

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