title: Target specificity of the E3 ligase LUBAC for ubiquitin and NEMO relies on different minimal requirements.
abstract: The ubiquitination of NEMO with linear ubiquitin chains by the E3-ligase LUBAC is important for the activation of the canonical NF-κB pathway. NEMO ubiquitination requires a dual target specificity of LUBAC, priming on a lysine on NEMO and chain elongation on the N terminus of the priming ubiquitin. Here we explore the minimal requirements for these specificities. Effective linear chain formation requires a precise positioning of the ubiquitin N-terminal amine in a negatively charged environment on the top of ubiquitin. Whereas the RBR-LDD region on HOIP is sufficient for targeting the ubiquitin N terminus, the priming lysine modification on NEMO requires catalysis by the RBR domain of HOIL-1L as well as the catalytic machinery of the RBR-LDD domains of HOIP. Consequently, target specificity toward NEMO is determined by multiple LUBAC components, whereas linear ubiquitin chain elongation is realized by a specific interplay between HOIP and ubiquitin.
authors.affiliation: From the Division of Biochemistry and.
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Smit
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van Dijk
authors.forename: Dris
authors.initials: D
authors.lastname: El Atmioui
authors.forename: Remco
authors.initials: R
authors.lastname: Merkx
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
mesh_terms: D002384:Catalysis; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C491731:IKBKG protein, human; D009097:Multienzyme Complexes; D025801:Ubiquitin; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase
keywords: E3 Ubiquitin Ligase; Enzyme Mechanisms; LUBAC; Linear Ubiquitin Chain; Molecular Biology; NF-κB (NF-KB); RNF31; Ubiquitination
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