Structural basis for the simultaneous recognition of NEMO and acceptor ubiquitin by the HOIP NZF1 domain

Structural basis for the simultaneous recognition of NEMO and acceptor ubiquitin by the HOIP NZF1 domain

Ubiquitination of NEMO by the linear ubiquitin chain assembly complex (LUBAC) is essential for activating the canonical NF-κB signaling pathway. While the NZF1 domain of the HOIP subunit of LUBAC recognizes the NEMO substrate, it is unclear how it cooperates with the catalytic domains in the ubiquit...

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Bibliographic Details
Published in:Scientific reports Vol. 12; no. 1; p. 12241
Main Authors: Rahighi, Simin, Iyer, Mamta, Oveisi, Hamid, Nasser, Sammy, Duong, Vincent
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 18-07-2022
Nature Publishing Group
Nature Portfolio
Subjects:
631/1647/2258/1266
631/45
Amino acids
Binding sites
Crystal structure
Humanities and Social Sciences
Hydrogen bonds
Kinases
multidisciplinary
NF-κB protein
Proteins
Science
Science (multidisciplinary)
Signal transduction
Symmetry
Ubiquitin
Ubiquitination
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Summary:Ubiquitination of NEMO by the linear ubiquitin chain assembly complex (LUBAC) is essential for activating the canonical NF-κB signaling pathway. While the NZF1 domain of the HOIP subunit of LUBAC recognizes the NEMO substrate, it is unclear how it cooperates with the catalytic domains in the ubiquitination process. Here, we report a crystal structure of NEMO in complex with HOIP NZF1 and linear diubiquitin chains, in which the two proteins bind to distinct sites on NEMO. Moreover, the NZF1 domain simultaneously interacts with NEMO and Ile44 surface of a proximal ubiquitin from a linear diubiquitin chain, where the C-term tail of the ubiquitin is in the proximity of the NEMO ubiquitination site (Lys285). We further propose a model for the linear ubiquitination of NEMO by HOIP. In the model, NZF1 binds the monoubiquitinated NEMO and recruits the catalytic domains to the ubiquitination site, thereby ensuring site-specific ubiquitination of NEMO.
Bibliography:ObjectType-Article-1
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content type line 23
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-16193-4