Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation
Open accessPublished version of a preprint
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/C CDH1: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 (CDH1 α1 ) in the APC/C CDH1: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.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Highly accurate protein structure prediction for the human proteome
Tunyasuvunakool, K., Adler, J., Wu, Z., Green, T., Zielinski, M., Žídek, A., Bridgland, A., Cowie, A., Meyer, C., Laydon, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03828-1 · Cited by 3,025 · see citing works
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Molecular mechanism of APC/C activation by mitotic phosphorylation
Zhang, S., Chang, L., Alfieri, C., Zhang, Z., Yang, J., Maslen, S., Skehel, M., & Barford, D. (2016) · Nature · doi:10.1038/nature17973 · Cited by 203 · see citing works
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- Authors
- Höfler, A., Yu, J., Yang, J., Zhang, Z., Chang, L., McLaughlin, S. H., Grime, G. W., Garman, E. F., Boland, A., & Barford, D.
- Affiliations
- University of Geneva (CH)
- MRC Laboratory of Molecular Biology (GB)
- University of Surrey (GB)
- University of Oxford (GB)
- Corresponding author
- Boland, Andreas
- Barford, David
- ORCID
- Venue
- Nature Communications
- Published
- 2024-11-21
- Volume
- 15
- Issue
- 1
- Pages
- 10074-10074
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11579458
- OpenAlex
- W4404532716
- Cited by
- 18
- References
- 4
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 4
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- RCUK | Medical Research Council (MC_UP_1201/6)
- Cancer Research UK (C576/A14109)
- Swiss Cancer League
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- anaphase-promoting complex, CDH1, Emi1, CDC20, APC2, intrinsically disordered regions, protein complex structure, cell cycle regulation, spindle assembly checkpoint, protein assembly
- MeSH terms
- Humans, Models, Molecular, Protein Binding, Zinc, Antigens, CD, Cadherins, Cell Cycle Proteins, Cryoelectron Microscopy, Anaphase-Promoting Complex-Cyclosome, Cdc20 Proteins, Cdh1 Proteins
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