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PreprintCited by 8Ubiquitin and proteasome pathwaysMicrotubule and mitosis dynamicsCancer-related Molecular Pathways

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A comparative study of the cryo-EM structures of S. cerevisiae and human anaphase-promoting complex/cyclosome (APC/C)

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Vazquez-Fernandez, Ester, Yang, Jing, Zhang, Ziguo, Andreeva, Antonina E., Emsley, Paul, Barford, David·2024·eLife
DOI 10.1101/2024.06.19.599685PMC PMC11473103

Preprint — published as 10.7554/elife.100821.3 · Paper page

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Abstract

The anaphase-promoting complex/cyclosome (APC/C) is a large multi-subunit E3 ubiquitin ligase that controls progression through the cell cycle by orchestrating the timely proteolysis of mitotic cyclins and other cell cycle regulatory proteins. Although structures of multiple human APC/C complexes have been extensively studied over the past decade, the S. cerevisiae APC/C has been less extensively investigated. Here, we describe medium resolution structures of three S. cerevisiae APC/C complexes: unphosphorylated apo-APC/C and the ternary APC/C CDH1 -substrate complex, and phosphorylated apo-APC/C. Whereas the overall architectures of human and S. cerevisiae APC/C are conserved, as well as the mechanism of CDH1 inhibition by CDK-phosphorylation, specific variations exist, including striking differences in the mechanism of coactivator-mediated stimulation of E2 binding, and the activation of APC/C CDC20 by phosphorylation. In contrast to human APC/C in which coactivator induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, in S. cerevisiae apo-APC/C the catalytic module is already positioned to bind E2. Furthermore, we find no evidence of a phospho-regulatable auto-inhibitory segment of APC1, that in the unphosphorylated human APC/C, sterically blocks the CDC20 C-box binding site of APC8. Thus, although the functions of APC/C are conserved from S. cerevisiae to humans, molecular details relating to their regulatory mechanisms differ.

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Metadata

Authors
Vazquez-Fernandez, E., Yang, J., Zhang, Z., Andreeva, A. E., Emsley, P., & Barford, D.
Affiliations
MRC Laboratory of Molecular Biology (GB)
Corresponding author
Barford, David
ORCID
Venue
eLife
Publisher
openRxiv
Published
2024-06-20
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2024.06.19.599685
PMC
PMC11473103
OpenAlex
W4403381822
Cited by
8
References
2
Citations by year
2026: 5 · 2025: 2 · 2024: 1
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • UK Research and Innovation (MC_UP_1201/6)
  • Cancer Research UK (C576/A14109)
  • Medical Research Council (MC_UP_1201/6)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
anaphase-promoting complex, Saccharomyces cerevisiae, E3 ubiquitin ligase, CDH1, CDC20, CDK phosphorylation, cell cycle regulation, protein complex structure
MeSH terms
Humans, Phosphorylation, Protein Conformation, Saccharomyces cerevisiae, Cryoelectron Microscopy, Saccharomyces cerevisiae Proteins, Anaphase-Promoting Complex-Cyclosome

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