title: The human otubain2-ubiquitin structure provides insights into the cleavage specificity of poly-ubiquitin-linkages.
abstract: 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.
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7FZ, United Kingdom; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21 Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Altun
authors.affiliation: Division of Structural Biology, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, United Kingdom.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Walter
authors.affiliation: Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford, OX1 3DQ, United Kingdom.
authors.forename: Holger B
authors.initials: HB
authors.lastname: Kramer
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21 Stockholm, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Herr
authors.affiliation: Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Iphöfer
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 21 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Boström
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: David
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7FZ, United Kingdom.
authors.forename: Alia
authors.initials: A
authors.lastname: Komsany
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7FZ, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ternette
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Navon
authors.affiliation: Division of Structural Biology, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, United Kingdom.
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.affiliation: Division of Structural Biology, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7BN, United Kingdom.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, Roosevelt Drive, University of Oxford, Oxford, OX3 7FZ, United Kingdom.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013869:Thiolester Hydrolases / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D025821:Polyubiquitin; C496399:OTUB2 protein, human; D013869:Thiolester Hydrolases