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  Mechanism of APC/C-CDC20 activation by mitotic phosphorylation.

Qiao, R. P., Weissmann, F., Yamaguchi, M., Brown, N. G., VanderLinden, R., Imre, R., et al. (2016). Mechanism of APC/C-CDC20 activation by mitotic phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 113(19), E2570-E2578. doi:10.1073/pnas.1604929113.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6B75-8 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-0B8F-F
Genre: Journal Article

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 Creators:
Qiao, R. P., Author
Weissmann, F., Author
Yamaguchi, M., Author
Brown, N. G., Author
VanderLinden, R., Author
Imre, R., Author
Jarvis, M. A., Author
Brunner, M. R., Author
Davidson, I. F., Author
Litos, G., Author
Haselbach, D.1, Author              
Mechtler, K., Author
Stark, H.2, Author              
Schulman, B. A., Author
Peters, J. M., Author
Affiliations:
1Research Group of 3D Electron Cryo-Microscopy, MPI for Biophysical Chemistry, Max Planck Society, ou_578577              
2Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              

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Free keywords: cell cycle; mitosis; APC/C; CDC20; phosphorylation
 Abstract: Chromosome segregation and mitotic exit are initiated by the 1.2-MDa ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) and its coactivator CDC20 (cell division cycle 20). To avoid chromosome missegregation, APC/C-CDC20 activation is tightly controlled. CDC20 only associates with APC/C in mitosis when APC/C has become phosphorylated and is further inhibited by a mitotic checkpoint complex until all chromosomes are bioriented on the spindle. APC/C contains 14 different types of subunits, most of which are phosphorylated in mitosis on multiple sites. However, it is unknown which of these phospho-sites enable APC/C-CDC20 activation and by which mechanism. Here we have identified 68 evolutionarily conserved mitotic phosphosites on human APC/C bound to CDC20 and have used the biGBac technique to generate 47 APC/C mutants in which either all 68 sites or subsets of them were replaced by nonphosphorylatable or phospho- mimicking residues. The characterization of these complexes in substrate ubiquitination and degradation assays indicates that phosphorylation of an N-terminal loop region in APC1 is sufficient for binding and activation of APC/C by CDC20. Deletion of the N-terminal APC1 loop enables APC/C-CDC20 activation in the absence of mitotic phosphorylation or phospho-mimicking mutations. These results indicate that binding of CDC20 to APC/C is normally prevented by an autoinhibitory loop in APC1 and that its mitotic phosphorylation relieves this inhibition. The predicted location of the N-terminal APC1 loop implies that this loop controls interactions between the N-terminal domain of CDC20 and APC1 and APC8. These results reveal how APC/C phosphorylation enables CDC20 to bind and activate the APC/C in mitosis.

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Language(s): eng - English
 Dates: 2016-04-25
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1604929113
 Degree: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 113 (19) Sequence Number: - Start / End Page: E2570 - E2578 Identifier: -