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  NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly

Baek, K., Krist, D. T., Prabu, J. R., Hill, S., Klügel, M., Neumaier, L.-M., et al. (2020). NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature, 578, 461-466. doi:10.1038/s41586-020-2000-y.

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 Creators:
Baek, Kheewong1, Author              
Krist, David T.1, Author              
Prabu, J. Rajan1, Author              
Hill, Spencer2, Author
Klügel, Maren1, Author              
Neumaier, Lisa-Marie1, Author              
von Gronau, Susanne1, Author              
Kleiger, Gary2, Author
Schulman, Brenda A.1, 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: KAPPA-B-ALPHA; RING E3 LIGASE; BETA-TRCP; COMPLEX REVEALS; PROTEIN; SCF; MECHANISM; ACTIVATION; SUBSTRATE; DESTRUCTION
 Abstract: Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation(1), which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8(2-6). However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1(beta-TRCP) promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated I kappa B alpha. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin-RING proteins. A cryo-electron microscopy structure provides insights into the activation of cullin-RING E3 ligases by NEDD8 and the consequent catalysis of ubiquitylation reactions.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000513111200004
DOI: 10.1038/s41586-020-2000-y
 Degree: -

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Project name : ERC Advanced Investigator Grant Nedd8Activate to B.A.S.
Grant ID : -
Funding program : -
Funding organization : European Commission

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 578 Sequence Number: - Start / End Page: 461 - 466 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238