Molecular basis and regulation of OTULIN-LUBAC interaction
<p style="text-align:justify;"> 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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2014
|
| _version_ | 1826312334954463232 |
|---|---|
| author | Elliott, PR Nielsen, SV Marco-Casanova, P Fiil, BK Keusekotten, K Mailand, N Freund, SMV Gyrd-Hansen, M Komander, D |
| author_facet | Elliott, PR Nielsen, SV Marco-Casanova, P Fiil, BK Keusekotten, K Mailand, N Freund, SMV Gyrd-Hansen, M Komander, D |
| author_sort | Elliott, PR |
| collection | OXFORD |
| description | <p style="text-align:justify;"> 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. </p> |
| first_indexed | 2024-03-07T08:27:30Z |
| format | Journal article |
| id | oxford-uuid:52dfdf76-5d77-4856-9867-e65cf0e2110f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:27:30Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:52dfdf76-5d77-4856-9867-e65cf0e2110f2024-02-22T14:00:37ZMolecular basis and regulation of OTULIN-LUBAC interactionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:52dfdf76-5d77-4856-9867-e65cf0e2110fEnglishSymplectic Elements at OxfordElsevier2014Elliott, PRNielsen, SVMarco-Casanova, PFiil, BKKeusekotten, KMailand, NFreund, SMVGyrd-Hansen, MKomander, D <p style="text-align:justify;"> 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. </p> |
| spellingShingle | Elliott, PR Nielsen, SV Marco-Casanova, P Fiil, BK Keusekotten, K Mailand, N Freund, SMV Gyrd-Hansen, M Komander, D Molecular basis and regulation of OTULIN-LUBAC interaction |
| title | Molecular basis and regulation of OTULIN-LUBAC interaction |
| title_full | Molecular basis and regulation of OTULIN-LUBAC interaction |
| title_fullStr | Molecular basis and regulation of OTULIN-LUBAC interaction |
| title_full_unstemmed | Molecular basis and regulation of OTULIN-LUBAC interaction |
| title_short | Molecular basis and regulation of OTULIN-LUBAC interaction |
| title_sort | molecular basis and regulation of otulin lubac interaction |
| work_keys_str_mv | AT elliottpr molecularbasisandregulationofotulinlubacinteraction AT nielsensv molecularbasisandregulationofotulinlubacinteraction AT marcocasanovap molecularbasisandregulationofotulinlubacinteraction AT fiilbk molecularbasisandregulationofotulinlubacinteraction AT keusekottenk molecularbasisandregulationofotulinlubacinteraction AT mailandn molecularbasisandregulationofotulinlubacinteraction AT freundsmv molecularbasisandregulationofotulinlubacinteraction AT gyrdhansenm molecularbasisandregulationofotulinlubacinteraction AT komanderd molecularbasisandregulationofotulinlubacinteraction |