Molecular basis and regulation of OTULIN-LUBAC interaction

The linear ubiquitin (Ub) chain assembly complex (LUBAC) generates Met1-linked "linear" Ub chains that regulate the activation of the nuclear factor κB (NFκB) transcription factor and other processes. We recently discovered OTULIN as a deubiquitinase that specifically cleaves Met1-linked p...

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Vydané v:Molecular cell Ročník 54; číslo 3; s. 335
Hlavní autori: Elliott, Paul R, Nielsen, Sofie V, Marco-Casanova, Paola, Fiil, Berthe Katrine, Keusekotten, Kirstin, Mailand, Niels, Freund, Stefan M V, Gyrd-Hansen, Mads, Komander, David
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 08.05.2014
Predmet:
Amino Acid Sequence
Binding Sites
Crystallography, X-Ray
Endopeptidases - chemistry
Endopeptidases - metabolism
HEK293 Cells
Humans
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Protein Structure, Secondary
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
ISSN:1097-4164, 1097-4164
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Popis
Shrnutí:The linear ubiquitin (Ub) chain assembly complex (LUBAC) generates Met1-linked "linear" Ub chains that regulate the activation of the nuclear factor κB (NFκB) transcription factor and other processes. We recently discovered OTULIN as a deubiquitinase that specifically cleaves Met1-linked polyUb. Now, we show that OTULIN binds via a conserved PUB-interacting motif (PIM) to the PUB domain of the LUBAC component HOIP. Crystal structures and nuclear magnetic resonance experiments reveal the molecular basis for the high-affinity interaction and explain why OTULIN binds the HOIP PUB domain specifically. Analysis of LUBAC-induced NFκB signaling suggests that OTULIN needs to be present on LUBAC in order to restrict Met1-polyUb signaling. Moreover, LUBAC-OTULIN complex formation is regulated by OTULIN phosphorylation in the PIM. Phosphorylation of OTULIN prevents HOIP binding, whereas unphosphorylated OTULIN is part of the endogenous LUBAC complex. Our work exemplifies how coordination of ubiquitin assembly and disassembly activities in protein complexes regulates individual Ub linkage types.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2014.03.018