Insights into Degron Recognition by APC/C Coactivators from the Structure of an Acm1-Cdh1 Complex

• DOI: 10.1016/j.molcel.2013.04.024
• Publication Date: 2013-05-23T15:53:38Z
• Authors: Jun He; William C.H. Chao; Ziguo Zhang; Jing Yang; Nora Cronin; David Barford
• Keywords: Degron; CDC20; Ubiquitin-Protein Ligases

The anaphase-promoting complex/cyclosome (APC/C) regulates sister chromatid segregation and the exit from mitosis. Selection of most APC/C substrates is controlled by coactivator subunits (either Cdc20 or Cdh1) that interact with substrate destruction motifs--predominantly the destruction (D) box and KEN box degrons. How coactivators recognize D box degrons and how this is inhibited by APC/C regulatory proteins is not defined at the atomic level. Here, from the crystal structure of S. cerevisiae Cdh1 in complex with its specific inhibitor Acm1, which incorporates D and KEN box pseudosubstrate motifs, we describe the molecular basis for D box recognition. Additional interactions between Acm1 and Cdh1 identify a third protein-binding site on Cdh1 that is likely to confer coactivator-specific protein functions including substrate association. We provide a structural rationalization for D box and KEN box recognition by coactivators and demonstrate that many noncanonical APC/C degrons bind APC/C coactivators at the D box coreceptor.