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  CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

Kostrhon, S., Prabu, J. R., Baek, K., Horn-Ghetko, D., Gronau, S. v., Klügel, M., et al. (2021). CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation. Nature Chemical Biology, 17(10), 1075-1083. doi:10.1038/s41589-021-00858-8.

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 Creators:
Kostrhon, Sebastian1, Author              
Prabu, J. Rajan1, Author              
Baek, Kheewong1, Author              
Horn-Ghetko, Daniel1, Author
Gronau, Susanne von1, Author              
Klügel, Maren1, Author              
Basquin, Jerome2, Author              
Alpi, Arno F.1, Author              
Schulman, Brenda A.1, Author              
Affiliations:
1Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              
2Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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Free keywords: COMPLEX REVEALS; E3 LIGASE; CBF-BETA; CRYSTAL-STRUCTURE; ANKYRIN-REPEAT; PROTEIN; MECHANISM; BOX; APOBEC3G; INSIGHTSBiochemistry & Molecular Biology;
 Abstract: An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 23
 Publishing info: -
 Table of Contents: We thank D. Bollschweiler and T. Schäfer of the cryo-EM facility and we thank the crystallography facility at Max Planck Institute of Biochemistry.
 Rev. Type: -
 Degree: -

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Project name : grant agreement no. 789016-NEDD8Activate
Grant ID : 789016
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Nature Chemical Biology
  Other : Nat. Chem. Biol.
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: - Volume / Issue: 17 (10) Sequence Number: - Start / End Page: 1075 - 1083 Identifier: ISSN: 1552-4450
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000021290_1