An Ankyrin-repeat ubiquitin binding domain determines TRABID’s specificity for atypical ubiquitin chains

Eight different types of ubiquitin linkages are present in eukaryotic cells that regulate diverse biological processes. Proteins that mediate specific assembly and disassembly of atypical Lys6, Lys27, Lys29 and Lys33 linkages are mainly unknown. We here reveal how the human ovarian tumor (OTU) domain deubiquitinase (DUB) TRABID specifically hydrolyzes both Lys29- and Lys33-linked diubiquitin. A crystal structure of the extended catalytic domain reveals an unpredicted ankyrin repeat domain that precedes an A20-like catalytic core. NMR analysis identifies the ankyrin domain as a new ubiquitin-binding fold, which we have termed AnkUBD, and DUB assays in vitro and in vivo show that this domain is crucial for TRABID efficiency and linkage specificity. Our data are consistent with AnkUBD functioning as an enzymatic S1′ ubiquitin-binding site, which orients a ubiquitin chain so that Lys29 and Lys33 linkages are cleaved preferentially.

• Publication year

  2011

• Venue

  Nature Structural &Molecular Biology

• Publication date

  2011-12-11

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/nsmb.2169PMID 22157957PMCID 5260945
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The EDD E3 ubiquitin ligase ubiquitinates and up-regulates β-catenin

  2011cited by this paper
• Polyubiquitin Linkage Profiles in Three Models of Proteolytic Stress Suggest the Etiology of Alzheimer Disease*

  2011cited by this paper
• Traceless and Site-Specific Ubiquitination of Recombinant Proteins

  2011cited by this paper
• Faculty Opinions recommendation of The EDD E3 ubiquitin ligase ubiquitinates and up-regulates beta-catenin.

  2011cited by this paper
• Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains

  2011cited by this paper
• Structural Analysis of a Viral Ovarian Tumor Domain Protease from the Crimean-Congo Hemorrhagic Fever Virus in Complex with Covalently Bonded Ubiquitin

  2011cited by this paper
• Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease

  2011cited by this paper
• Total chemical synthesis of di-ubiquitin chains.

  2010cited by this paper
• Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling.

  2010cited by this paper
• Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase.

  2010cited by this paper
• Chemical Synthesis of Ubiquitin, Ubiquitin-Based Probes, and Diubiquitin**

  2010cited by this paper
• A20: from ubiquitin editing to tumour suppression

  2010cited by this paper
• Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne

  2010cited by this paper
• The HADDOCK web server for data-driven biomolecular docking

  2010cited by this paper
• Dali server: conservation mapping in 3D

  2010cited by this paper
• Structural basis and specificity of human otubain 1-mediated deubiquitination.

  2009cited by this paper
• Molecular discrimination of structurally equivalent Lys 63‐linked and linear polyubiquitin chains

  2009cited by this paper
• Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain

  2009cited by this paper
• Structural basis for specific recognition of Lys 63‐linked polyubiquitin chains by NZF domains of TAB2 and TAB3

  2009cited by this paper
• The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER.

  2009cited by this paper
• Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation.

  2009cited by this paper
• Breaking the chains: structure and function of the deubiquitinases

  2009cited by this paper
• The emerging complexity of protein ubiquitination.

  2009cited by this paper
• Ubiquitin-binding domains — from structures to functions

  2009cited by this paper
• K63‐specific deubiquitination by two JAMM/MPN+ complexes: BRISC‐associated Brcc36 and proteasomal Poh1

  2009cited by this paper
• Regulation of Virus-triggered Signaling by OTUB1- and OTUB2-mediated Deubiquitination of TRAF3 and TRAF6*

  2009cited by this paper
• K 63-specific deubiquitination by two JAMM / MPN þ complexes : BRISC-associated Brcc 36 and proteasomal Poh 1

  2009cited by this paper
• The expanding field of poly(ADP-ribosyl)ation reactions. ‘Protein Modifications: Beyond the Usual Suspects' Review Series

  2008cited by this paper
• Structure of the A20 OTU domain and mechanistic insights into deubiquitination.

  2008cited by this paper
• Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains

  2008cited by this paper
• Atypical ubiquitin chains: new molecular signals

  2008cited by this paper
• Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains

  2008cited by this paper
• Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20.

  2008cited by this paper
• Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.

  2008cited by this paper
• Structural Basis for Ubiquitin Recognition by the Otu1 Ovarian Tumor Domain Protein*

  2008cited by this paper
• Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains.

  2008cited by this paper
• Recognition of Polyubiquitin Isoforms by the Multiple Ubiquitin Binding Modules of Isopeptidase T*

  2008cited by this paper
• A Deubiquitinase That Regulates Type I Interferon Production

  2007cited by this paper
• Putative tumor suppressor EDD interacts with and up‐regulates APC

  2007cited by this paper
• Ankyrin repeat: a unique motif mediating protein-protein interactions.

  2006cited by this paper
• Molecular determinants of polyubiquitin linkage selection by an HECT ubiquitin ligase

  2006cited by this paper
• Itch/AIP4 mediates Deltex degradation through the formation of K29‐linked polyubiquitin chains

  2006cited by this paper
• A genomic and functional inventory of deubiquitinating enzymes.

  2005cited by this paper
• The Wnt signalling effector Dishevelled forms dynamic protein assemblies rather than stable associations with cytoplasmic vesicles

  2005cited by this paper
• Structural basis for recognition of 2′,5′‐linked oligoadenylates by human ribonuclease L

  2004cited by this paper
• The ankyrin repeat as molecular architecture for protein recognition

  2004cited by this paper
• Coot: model-building tools for molecular graphics.

  2004cited by this paper
• Crystal structure of human otubain 2

  2004cited by this paper
• AMSH is an endosome-associated ubiquitin isopeptidase

  2004cited by this paper
• HKL2MAP: a graphical user interface for macromolecular phasing with SHELX programs

  2004cited by this paper
• Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0.

  2003cited by this paper
• VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo

  2002cited by this paper
• Isolation and characterization of two novel A20-like proteins.

  2001cited by this paper
• A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly.

  1999cited by this paper
• Automated protein model building combined with iterative structure refinement

  1999cited by this paper
• NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.

  1997cited by this paper
• Improved sensitivity of HSQC spectra of exchanging protons at short interscan delays using a new fast HSQC (FHSQC) detection scheme that avoids water saturation.

  1995cited by this paper
• A Proteolytic Pathway That Recognizes Ubiquitin as a Degradation Signal (*)

  1995cited by this paper
• Culture Medium for Enterobacteria

  1974cited by this paper
• Electronic Reprint Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination Biological Crystallography Phenix: Building New Software for Automated Crystallographic Structure Determination

  year unknowncited by this paper

• Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway.

  2025cites this paper
• E3 ligase AREL1 controls perinuclear localization of lysosomes and supports Purkinje cell survival

  2025cites this paper
• OTU deubiquitinases in cancer pathogenesis and precision therapy.

  2025cites this paper
• Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation

  2025cites this paper
• Research progress of DUB enzyme in breast cancer

  2025cites this paper
• MINPP1 promotes ferroptosis in HBV-related hepatocellular carcinoma by regulating CTSB K33-linked deubiquitination via ZRANB1

  2025cites this paper
• CAPN15 is a non-proteasomal, ubiquitin-directed calpain protease that regulates cell adhesion by cleaving E-cadherin

  2025cites this paper
• Aging and diet alter the protein ubiquitylation landscape in the mouse brain

  2025cites this paper
• Synergizing Structure-Guided Photocaged Linear Diubiquitin-Dha with Biotinylated Linear-Fab for Time-Resolved Profiling of Interactors in Living Cells.

  2025cites this paper
• Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism

  2025cites this paper
• The Molecular Toolbox for Linkage Type‐Specific Analysis of Ubiquitin Signaling

  2025cites this paper
• The emerging roles of non-canonical ubiquitination in proteostasis and beyond

  2024cites this paper
• Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage

  2024cites this paper
• Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation

  2024cites this paper
• Dysregulation of deubiquitination in breast cancer.

  2024cites this paper
• Deubiquitinases as novel therapeutic targets for diseases

  2024cites this paper
• Architectonics of Ubiquitin Chains

  2024cites this paper
• Rapid turnover of CTLA4 is associated with a complex architecture of reversible ubiquitylation

  2024cites this paper
• Genetic Code Expansion Approaches to Decipher the Ubiquitin Code

  2024cites this paper
• crANKing up the infection: ankyrin domains in Rickettsiales and their role in host manipulation

  2024cites this paper
• Architectonics of Ubiquitin Chains (A Review)

  2024cites this paper
• Furin Egress from the TGN is Regulated by Membrane‐Associated RING‐CH Finger (MARCHF) Proteins and Ubiquitin‐Specific Protease 32 (USP32) via Nondegradable K33‐Polyubiquitination

  2024cites this paper
• N4BP1 functions as a dimerization-dependent linear ubiquitin reader which regulates TNF signalling

  2024cites this paper
• Demonstrating the importance of porcine reproductive and respiratory syndrome virus papain-like protease 2 deubiquitinating activity in viral replication by structure-guided mutagenesis

  2023cites this paper
• Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to 1 disrupt neurite growth 2

  2023influential citation
• Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth

  2023influential citation
• Deubiquitylating Enzymes in Cancer and Immunity

  2023cites this paper
• Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer

  2023cites this paper
• Ubiquitin ligase enzymes and de-ubiquitinating enzymes regulate innate immunity in the TLR, NLR, RLR, and cGAS-STING pathways

  2023cites this paper
• TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation

  2023cites this paper
• Characterisation of the OTU domain deubiquitinase complement of Toxoplasma gondii

  2023cites this paper
• Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm

  2023cites this paper
• HECTD1 is both a positive regulator and substrate of caspase-3 activity during apoptotic cell death

  2023cites this paper
• Synthetic Diubiquitin Fluorogenic Substrates to Study DUBs.

  2023cites this paper
• TRABID targets DDB2 for deubiquitination to promote proliferation of hepatocellular carcinoma cells.

  2022cites this paper
• The E3 ubiquitin ligase HECTD1 contributes to cell proliferation through an effect on mitosis

  2022cites this paper
• A Feedback Regulatory Loop Involving dTrbd/dTak1 in Controlling IMD Signaling in Drosophila Melanogaster

  2022cites this paper
• Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

  2022cites this paper
• Histone Demethylase JMJD2D: A Novel Player in Colorectal and Hepatocellular Cancers

  2022cites this paper
• Structural basis for the linkage specificity of ubiquitin-binding domain and deubiquitinase.

  2022cites this paper
• Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis.

  2022cites this paper
• Deubiquitylating enzymes: potential target in autoimmune diseases

  2021cites this paper
• K29-linked ubiquitin signaling regulates proteotoxic stress response and cell cycle

  2021cites this paper
• Beyond K48 and K63: non-canonical protein ubiquitination

  2021cites this paper
• The linear ubiquitin chain assembly complex (LUBAC) generates heterotypic ubiquitin chains

  2021cites this paper
• Regulation of autophagy by VPS34 branched ubiquitination controls proteostasis and liver metabolism

  2021cites this paper
• VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism

  2021cites this paper
• TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains.

  2021cites this paper
• Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2

  2021cites this paper
• Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

  2021cites this paper
• The E3 ubiquitin ligase HECTD1 contributes to cell cycle progression through an effect on mitosis

  2021cites this paper
• Deubiquitinases: From mechanisms to their inhibition by small molecules.

  2021cites this paper
• Diubiquitin-Based NMR Analysis: Interactions Between Lys6-Linked diUb and UBA Domain of UBXN1

  2020cites this paper
• -A novel polyubiquitin chain linkage formed by viral Ubiquitin is resistant to host deubiquitinating enzymes.

  2020cites this paper
• The linear ubiquitin chain assembly complex generates heterotypic ubiquitin chains

  2020cites this paper
• Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases

  2020cites this paper
• The Ubiquitin System in Alzheimer's Disease.

  2020cites this paper
• Interaction Landscape of K29-Linked Ubiquitin Signaling Revealed by a Linkage-Specific Synthetic Antigen-Binding Fragment

  2020cites this paper
• The deubiquitinase TRABID stabilizes the K29/K48-specific E3 ubiquitin ligase HECTD1

  2020influential citation
• The role of ubiquitination in tumorigenesis and targeted drug discovery

  2020cites this paper
• Identification and characterization of diverse OTU deubiquitinases in bacteria

  2020cites this paper
• Deubiquitinating enzymes (DUBs): DoUBle-edged swords in CNS autoimmunity

  2020cites this paper
• Analysis of ubiquitin signaling and chain topology cross-talk.

  2020cites this paper
• Gene expression profile of CD14+ blood monocytes following lifestyle-induced weight loss in individuals with metabolic syndrome

  2020cites this paper
• Identification and characterization of diverse OTU deubiquitinases in bacteria

  2020cites this paper
• Branching and Mixing: New Signals of the Ubiquitin Signaling System

  2020cites this paper
• DEUBIQUITINATING ENZYMES PROMOTE CANCER PROGRESSION AND METASTASIS VIA REGULATING PROTEIN STABILITY

  2019cites this paper
• Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity

  2019cites this paper
• Exploring the suitability of RanBP2-type Zinc Fingers for RNA-binding protein design

  2019cites this paper
• TUBE and UbiCRest assays for elucidating polyubiquitin modifications in protein complexes.

  2019cites this paper
• The function and regulation of OTU deubiquitinases

  2019cites this paper
• OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling.

  2018cites this paper
• Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by SQSTM1/p62

  2018cites this paper
• ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer.

  2018cites this paper
• Trabid inhibits hepatocellular carcinoma growth and metastasis by cleaving RNF8-induced K63 ubiquitination of Twist1

  2018cites this paper
• Deubiquitinating Enzymes Related to Autophagy: New Therapeutic Opportunities?

  2018cites this paper
• The deubiquitinase MYSM1 dampens NOD2-mediated inflammation and tissue damage by inactivating the RIP2 complex

  2018cites this paper
• Role of HECT ubiquitin protein ligases in Arabidopsis thaliana

  2018cites this paper
• Decoding lysine-11 signals in ubiquitination

  2018cites this paper
• Identification of Proteins Interacting with Ubiquitin Chains.

  2017cites this paper
• How Chemical Synthesis of Ubiquitin Conjugates Helps To Understand Ubiquitin Signal Transduction.

  2017cites this paper
• Identifizierung von Interaktoren von Ubiquitinketten

  2017cites this paper
• Parkinson’s Disease-associated proteins: studying their role in mitophagy with cellular and Drosophila models

  2017cites this paper
• Activity‐Based Probes for HECT E3 Ubiquitin Ligases

  2017cites this paper
• An Interaction Landscape of Ubiquitin Signaling.

  2017cites this paper
• Profiling the Activity of Deubiquitinating Enzymes Using Chemically Synthesized Ubiquitin-Based Probes.

  2017cites this paper
• Mechanisms of Deubiquitinase Specificity and Regulation.

  2017cites this paper
• Internally tagged ubiquitin: a tool to identify linear polyubiquitin-modified proteins by mass spectrometry

  2017cites this paper
• The Molecular Basis for Ubiquitin and Ubiquitin-like Specificities in Bacterial Effector Proteases

  2016cites this paper
• Ubiquitin chain diversity at a glance

  2016cites this paper
• The Search for Deconjugating Enzymes of FAT10

  2016cites this paper
• The recognition of ubiquitinated proteins by the proteasome

  2016cites this paper
• Ubiquitin modifications

  2016cites this paper
• DUBbing Cancer: Deubiquitylating Enzymes Involved in Epigenetics, DNA Damage and the Cell Cycle As Therapeutic Targets

  2016cites this paper
• Chemical and semisynthetic approaches to study and target deubiquitinases.

  2016cites this paper
• The increasing complexity of the ubiquitin code

  2016cites this paper
• Chemical ubiquitination for decrypting a cellular code

  2016cites this paper
• Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne

  2016cites this paper
• SPATA2 promotes CYLD activity and regulates TNF‐induced NF‐κB signaling and cell death

  2016influential citation
• The use of unnatural amino acids to study and engineer protein function.

  2016cites this paper