An ankyrin-repeat ubiquitin-binding domain determines TRABID's specificity for atypical ubiquitin chains

Julien D F Licchesi; Juliusz Mieszczanek; Tycho E T Mevissen; Trevor J Rutherford; Masato Akutsu; Satpal Virdee; Farid El Oualid; Jason W Chin; Huib Ovaa; Mariann Bienz; David Komander

doi:10.1038/nsmb.2169

An ankyrin-repeat ubiquitin-binding domain determines TRABID's specificity for atypical ubiquitin chains

Julien D F Licchesi, Juliusz Mieszczanek, Tycho E T Mevissen, Trevor J Rutherford, Masato Akutsu, Satpal Virdee, Farid El Oualid, Jason W Chin, Huib Ovaa, Mariann Bienz, David Komander

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

96 Citations (SciVal)

Abstract

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.

Original language	English
Pages (from-to)	62-71
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	19
Issue number	1
Early online date	11 Dec 2011
DOIs	https://doi.org/10.1038/nsmb.2169
Publication status	Published - 2012

Keywords

amino acid sequence
animals
ankyrin repeat
binding sites
blotting, western
COS cells
catalytic domain
cercopithecus aethiops
crystallography, X-ray
endopeptidases
fluorescence recovery after photobleaching
green fluorescent proteins
HEK293 cells
humans
lysine
magnetic resonance spectroscopy
microscopy, confocal
models, molecular
molecular sequence data
mutation
protein binding
protein structure, tertiary
sequence homology, amino acid
ubiquitin
ubiquitin thiolesterase

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abstract = "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.",

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author = "Licchesi, {Julien D F} and Juliusz Mieszczanek and Mevissen, {Tycho E T} and Rutherford, {Trevor J} and Masato Akutsu and Satpal Virdee and {El Oualid}, Farid and Chin, {Jason W} and Huib Ovaa and Mariann Bienz and David Komander",

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AU - Licchesi, Julien D F

AU - Mieszczanek, Juliusz

AU - Mevissen, Tycho E T

AU - Rutherford, Trevor J

AU - Akutsu, Masato

AU - Virdee, Satpal

AU - El Oualid, Farid

AU - Chin, Jason W

AU - Ovaa, Huib

AU - Bienz, Mariann

AU - Komander, David

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N2 - 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.

AB - 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.

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KW - crystallography, X-ray

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KW - magnetic resonance spectroscopy

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KW - models, molecular

KW - molecular sequence data

KW - mutation

KW - protein binding

KW - protein structure, tertiary

KW - sequence homology, amino acid

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JO - Nature Structural and Molecular Biology

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ER -

An ankyrin-repeat ubiquitin-binding domain determines TRABID's specificity for atypical ubiquitin chains

Abstract

Keywords

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