The multi-subunit anaphase-promoting complex/cyclosome (APC/C) is a master regulator of cell division. It controls progression through the cell cycle by timely marking mitotic cyclins, securin and other cell cycle regulatory proteins for degradation via the ubiquitin-proteasome pathway. The APC/C itself is regulated by the sequential action of its coactivator subunits CDC20 and CDH1, post-translational modifications (see our work on CDK1/cyclin B1), and its inhibitory binding partners EMI1 and the mitotic checkpoint complex (MCC). We determined the structures of human APC/C bound to CDH1 and EMI1 and apo-APC/C at 2.9 Å and 3.2 Å, respectively, providing novel insights into the regulation of APC/C activity. The high resolution maps allowed the unambigious assignment of a previously unassigned α-helix to the N-terminus of CDH1 (CDH1α1) in the ternary complex. CDH1α1 binds at the APC1-APC8 interface, thereby interacting with a loop segment of APC1 through electrostatic interactions only provided by CDH1 but not CDC20. We also indentified a novel zinc-binding module in APC2, and confirmed the presence of zinc ions experimentally. Finally, due to the higher resolution and well defined density of these maps we were able to build, aided by AlphaFold predictions, several intrinsically disordered regions in different APC/C subunits that play a fundamental role in proper complex assembly. The work is summarised in the video, generated by Anna Höfler.

https://www.nature.com/articles/s41467-024-54398-5