3ZNX

Crystal structure of the OTU domain of OTULIN D336A mutant

Summary for 3ZNX

• Entry DOI: 10.2210/pdb3znx/pdb
• Related: 3ZNV
• Descriptor: PROTEIN FAM105B, CALCIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 32234.46

Authors

Keusekotten, K.,Elliott, P.R.,Glockner, L.,Kulathu, Y.,Wauer, T.,Krappmann, D.,Hofmann, K.,Komander, D. (deposition date: 2013-02-18, release date: 2013-06-26, Last modification date: 2023-12-20)

Primary citation

Keusekotten, K.,Elliott, P.R.,Glockner, L.,Fiil, B.K.,Damgaard, R.B.,Kulathu, Y.,Wauer, T.,Hospenthal, M.K.,Gyrd-Hansen, M.,Krappmann, D.,Hofmann, K.,Komander, D.
Otulin Antagonizes Lubac Signaling by Specifically Hydrolyzing met1-Linked Polyubiquitin.
Cell(Cambridge,Mass.), 153:1312-, 2013

PubMed Abstract: The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor κB (NF-κB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1-specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-κB responses to LUBAC, TNFα, and poly(I:C) and sensitizes cells to TNFα-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFα-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling.

PubMed: 23746843
DOI: 10.1016/J.CELL.2013.05.014

Experimental method

X-RAY DIFFRACTION (1.35 Å)