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  RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex.

Brown, N. G., VanderLinden, R., Watson, E. R., Qiao, R. P., Grace, C. R. R., Yamaguchi, M., et al. (2015). RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex. Proceedings of the National Academy of Sciences of the United States of America, 112(17), 5272-5279. doi:10.1073/pnas.1504161112.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-832B-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-80DE-F
Genre: Journal Article

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 Creators:
Brown, N. G., Author
VanderLinden, R., Author
Watson, E. R., Author
Qiao, R. P., Author
Grace, C. R. R., Author
Yamaguchi, M., Author
Weissmann, F., Author
Frye, J. J., Author
Dube, P.1, Author              
Cho, S. E., Author
Actis, M. L., Author
Rodrigues, P., Author
Fujii, N., Author
Peters, J. M., Author
Stark, H.1, Author              
Schulman, B. A., Author
Affiliations:
1Research Group of 3D Electron Cryo-Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578577              

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Free keywords: ubiquitin; anaphase-promoting complex; cullin; E3; electron microscopy
 Abstract: For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2 similar to Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaborates with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING-E2 similar to Ub catalytic modules such as APC11-UBCH10 similar to Ub collide with distally tethered disordered substrates remains poorly understood. We report structural mechanisms of UBCH10 recruitment to APC(CDH1) and substrate ubiquitination. Unexpectedly, in addition to binding APC11's RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APC(CDH1)-UBCH10 similar to Ub-substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin-RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin-RING-E2 interactions establish APC's specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. We propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3-E2 similar to Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation.

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Language(s): eng - English
 Dates: 2015-04-28
 Publication Status: Published online
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1504161112
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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: 112 (17) Sequence Number: - Start / End Page: 5272 - 5279 Identifier: -