Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15.
Structure
; 27(4): 590-605.e5, 2019 04 02.
Article
em En
| MEDLINE
| ID: mdl-30713027
ABSTRACT
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 ß 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Ubiquitina
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Ubiquitina-Proteína Ligases
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Fator de Crescimento Transformador beta1
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Proteases Específicas de Ubiquitina
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Proteínas com Motivo Tripartido
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Structure
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Canadá