Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.molcel.2014.03.018

Type

Journal article

Journal

Molecular cell

Publication Date

05/2014

Volume

54

Pages

335 - 348

Addresses

Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.

Keywords

Humans, Endopeptidases, Ubiquitin-Protein Ligases, Crystallography, X-Ray, Nuclear Magnetic Resonance, Biomolecular, Protein Processing, Post-Translational, Binding Sites, Amino Acid Sequence, Protein Structure, Secondary, Protein Binding, Phosphorylation, Models, Molecular, Molecular Sequence Data, Protein Interaction Domains and Motifs, HEK293 Cells, Hydrophobic and Hydrophilic Interactions