Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation
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 co...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54398-5 |
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| author | Anna Höfler Jun Yu Jing Yang Ziguo Zhang Leifu Chang Stephen H. McLaughlin Geoffrey W. Grime Elspeth F. Garman Andreas Boland David Barford |
| author_facet | Anna Höfler Jun Yu Jing Yang Ziguo Zhang Leifu Chang Stephen H. McLaughlin Geoffrey W. Grime Elspeth F. Garman Andreas Boland David Barford |
| author_sort | Anna Höfler |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-589f354937f84c75bfa553a6d658d72c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-589f354937f84c75bfa553a6d658d72c2024-11-24T12:33:37ZengNature PortfolioNature Communications2041-17232024-11-0115111410.1038/s41467-024-54398-5Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulationAnna Höfler0Jun Yu1Jing Yang2Ziguo Zhang3Leifu Chang4Stephen H. McLaughlin5Geoffrey W. Grime6Elspeth F. Garman7Andreas Boland8David Barford9Department of Molecular and Cellular Biology, University of GenevaDepartment of Molecular and Cellular Biology, University of GenevaMRC Laboratory of Molecular BiologyMRC Laboratory of Molecular BiologyMRC Laboratory of Molecular BiologyMRC Laboratory of Molecular BiologyIon Beam Centre, Advanced Technology Institute, University of SurreyDepartment of Biochemistry, University of OxfordDepartment of Molecular and Cellular Biology, University of GenevaMRC Laboratory of Molecular BiologyAbstract 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.https://doi.org/10.1038/s41467-024-54398-5 |
| spellingShingle | Anna Höfler Jun Yu Jing Yang Ziguo Zhang Leifu Chang Stephen H. McLaughlin Geoffrey W. Grime Elspeth F. Garman Andreas Boland David Barford Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation Nature Communications |
| title | Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation |
| title_full | Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation |
| title_fullStr | Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation |
| title_full_unstemmed | Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation |
| title_short | Cryo-EM structures of apo-APC/C and APC/CCDH1:EMI1 complexes provide insights into APC/C regulation |
| title_sort | cryo em structures of apo apc c and apc ccdh1 emi1 complexes provide insights into apc c regulation |
| url | https://doi.org/10.1038/s41467-024-54398-5 |
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