The human otubain2-ubiquitin structure provides insights into the cleavage specificity of poly-ubiquitin-linkages

Ovarian tumor domain containing proteases cleave ubiquitin (Ub) and ubiquitin-like polypeptides from proteins. Here we report the crystal structure of human otubain 2 (OTUB2) in complex with a ubiquitin-based covalent inhibitor, Ub-Br2. The ubiquitin binding mode is oriented differently to how viral...

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Bibliographic Details
Published in:PloS one 2015-01, Vol.10 (1), p.e0115344-e0115344
Main Authors: Altun, Mikael, Walter, Thomas S, Kramer, Holger B, Herr, Patrick, Iphöfer, Alexander, Boström, Johan, David, Yael, Komsany, Alia, Ternette, Nicola, Navon, Ami, Stuart, David I, Ren, Jingshan, Kessler, Benedikt M
Format: Article
Language:English
Subjects:
Automation
Biochemistry
Biology
Biophysics
Chains
Coordination compounds
Crystal structure
Crystallization
Crystallography, X-Ray
Enzymatic activity
Enzyme activity
Enzymes
Humans
Interferon
Laboratories
Medicin och hälsovetenskap
Medicine
Models, Molecular
Polypeptides
Polyubiquitin - metabolism
Proteases
Protein Binding
Protein Structure, Tertiary
Proteins
Science
Selectivity
Substrates
Thiolester Hydrolases - metabolism
Ubiquitin
Ubiquitin - metabolism
Yeast
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Summary:Ovarian tumor domain containing proteases cleave ubiquitin (Ub) and ubiquitin-like polypeptides from proteins. Here we report the crystal structure of human otubain 2 (OTUB2) in complex with a ubiquitin-based covalent inhibitor, Ub-Br2. The ubiquitin binding mode is oriented differently to how viral otubains (vOTUs) bind ubiquitin/ISG15, and more similar to yeast and mammalian OTUs. In contrast to OTUB1 which has exclusive specificity towards Lys48 poly-ubiquitin chains, OTUB2 cleaves different poly-Ub linked chains. N-terminal tail swapping experiments between OTUB1 and OTUB2 revealed how the N-terminal structural motifs in OTUB1 contribute to modulating enzyme activity and Ub-chain selectivity, a trait not observed in OTUB2, supporting the notion that OTUB2 may affect a different spectrum of substrates in Ub-dependent pathways.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0115344