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  Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

Horn-Ghetko, D., Krist, D. T., Prabu, J. R., Baek, K., Mulder, M. P. C., Kluegel, M., et al. (2021). Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly. Nature, 590(7847), 671-676. doi:10.1038/s41586-021-03197-9.

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 Creators:
Horn-Ghetko, Daniel1, Author              
Krist, David T.1, Author              
Prabu, J. Rajan1, Author              
Baek, Kheewong1, Author              
Mulder, Monique P. C.2, Author
Kluegel, Maren1, Author              
Scott, Daniel C.2, Author
Ovaa, Huib2, Author
Kleiger, Gary2, Author
Schulman, Brenda1, Author              
Affiliations:
1Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              
2external, ou_persistent22              

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Free keywords: ACTIVITY-BASED PROBES; RING E3 LIGASE; STRUCTURAL BASIS; COMPLEX REVEALS; CRYSTAL-STRUCTURE; MECHANISM; PARKIN; SUBSTRATE; NEDD8; ACTIVATIONScience & Technology - Other Topics;
 Abstract: E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates(1,2). However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies(3-7). Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3-E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3-E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3-E3 super-assembly may therefore underlie widespread ubiquitylation.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 30
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 Table of Contents: -
 Rev. Type: Peer
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 590 (7847) Sequence Number: - Start / End Page: 671 - 676 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238