Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15
The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designe...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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CELL PRESS
2019
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| Online Access: | http://hdl.handle.net/20.500.11937/75729 |
| _version_ | 1848763536542531584 |
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| author | Teyra, J. Singer, A. Schmitges, F. Jaynes, P. Kit Leng Lui, S. Polyak, M. Fodil, N. Krieger, J. Tong, J. Schwerdtfeger, C. Brasher, B. Ceccarelli, DFJ Moffat, J. Sicheri, F. Moran, M. Gros, P. Eichhorn, Pieter Lenter, M. Boehmelt, G. Sidhu, S. |
| author_facet | Teyra, J. Singer, A. Schmitges, F. Jaynes, P. Kit Leng Lui, S. Polyak, M. Fodil, N. Krieger, J. Tong, J. Schwerdtfeger, C. Brasher, B. Ceccarelli, DFJ Moffat, J. Sicheri, F. Moran, M. Gros, P. Eichhorn, Pieter Lenter, M. Boehmelt, G. Sidhu, S. |
| author_sort | Teyra, J. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation. |
| first_indexed | 2025-11-14T11:05:01Z |
| format | Journal Article |
| id | curtin-20.500.11937-75729 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:05:01Z |
| publishDate | 2019 |
| publisher | CELL PRESS |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-757292019-06-11T04:09:46Z Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 Teyra, J. Singer, A. Schmitges, F. Jaynes, P. Kit Leng Lui, S. Polyak, M. Fodil, N. Krieger, J. Tong, J. Schwerdtfeger, C. Brasher, B. Ceccarelli, DFJ Moffat, J. Sicheri, F. Moran, M. Gros, P. Eichhorn, Pieter Lenter, M. Boehmelt, G. Sidhu, S. Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Biophysics Cell Biology CELL-CYCLE DEUBIQUITYLATING ENZYMES DEUBIQUITINATING ENZYMES E3 LIGASES PHOSPHORYLATION SPECIFICITY RECOGNITION CENTROSOME MODULATION DISCOVERY The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation. 2019 Journal Article http://hdl.handle.net/20.500.11937/75729 10.1016/j.str.2019.01.002 English CELL PRESS restricted |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Biophysics Cell Biology CELL-CYCLE DEUBIQUITYLATING ENZYMES DEUBIQUITINATING ENZYMES E3 LIGASES PHOSPHORYLATION SPECIFICITY RECOGNITION CENTROSOME MODULATION DISCOVERY Teyra, J. Singer, A. Schmitges, F. Jaynes, P. Kit Leng Lui, S. Polyak, M. Fodil, N. Krieger, J. Tong, J. Schwerdtfeger, C. Brasher, B. Ceccarelli, DFJ Moffat, J. Sicheri, F. Moran, M. Gros, P. Eichhorn, Pieter Lenter, M. Boehmelt, G. Sidhu, S. Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title | Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title_full | Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title_fullStr | Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title_full_unstemmed | Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title_short | Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15 |
| title_sort | structural and functional characterization of ubiquitin variant inhibitors of usp15 |
| topic | Science & Technology Life Sciences & Biomedicine Biochemistry & Molecular Biology Biophysics Cell Biology CELL-CYCLE DEUBIQUITYLATING ENZYMES DEUBIQUITINATING ENZYMES E3 LIGASES PHOSPHORYLATION SPECIFICITY RECOGNITION CENTROSOME MODULATION DISCOVERY |
| url | http://hdl.handle.net/20.500.11937/75729 |