Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation

Anna Höfler, Jun Yu, Jing Yang, Ziguo Zhang, Leifu Chang, Stephen H. McLaughlin, Geoffrey W. Grime, Elspeth F. Garman, Andreas Boland () and David Barford ()
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Anna Höfler: University of Geneva
Jun Yu: University of Geneva
Jing Yang: MRC Laboratory of Molecular Biology
Ziguo Zhang: MRC Laboratory of Molecular Biology
Leifu Chang: MRC Laboratory of Molecular Biology
Stephen H. McLaughlin: MRC Laboratory of Molecular Biology
Geoffrey W. Grime: University of Surrey
Elspeth F. Garman: University of Oxford
Andreas Boland: University of Geneva
David Barford: MRC Laboratory of Molecular Biology

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract APC/C is a multi-subunit complex that functions as a master regulator of cell division. It controls progression through the cell cycle by timely marking mitotic cyclins and other cell cycle regulatory proteins for degradation. The APC/C itself is regulated by the sequential action of its coactivator subunits CDC20 and CDH1, post-translational modifications, and its inhibitory binding partners EMI1 and the mitotic checkpoint complex. In this study, we took advantage of developments in cryo-electron microscopy to determine the structures of human APC/CCDH1:EMI1 and apo-APC/C at 2.9 Å and 3.2 Å resolution, respectively, providing insights into the regulation of APC/C activity. The high-resolution maps allow the unambiguous assignment of an α-helix to the N-terminus of CDH1 (CDH1α1) in the APC/CCDH1:EMI1 ternary complex. We also identify a zinc-binding module in APC2 that confers structural stability to the complex, and we confirm the presence of zinc ions experimentally. Finally, due to the higher resolution and well defined density of these maps, we are able to build, aided by AlphaFold predictions, several intrinsically disordered regions in different APC/C subunits that likely play a role in proper APC/C assembly and regulation of its activity.

Date: 2024
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DOI: 10.1038/s41467-024-54398-5

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