Journal
COMMUNICATIONS BIOLOGY
Volume 4, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-02802-x
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Funding
- JSPS KAKENHI [17K08625, 19H05289, 21H00276, 15H04293]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) from AMED [JP21am0101109]
- Nagase Science and Technology Foundation
- Grants-in-Aid for Scientific Research [21H00276, 19H05289, 15H04293, 17K08625] Funding Source: KAKEN
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This study identified amino acids 645-684 of USP8 as an autoinhibitory region and suggested that the release of USP8 autoinhibition may underlie Cushing's disease. The findings also indicate that 14-3-3 inhibits USP8 activity partly by enhancing the interaction between the WW-like and USP domains.
Ubiquitin-specific protease 8 (USP8) is a deubiquitinating enzyme involved in multiple membrane trafficking pathways. The enzyme activity is inhibited by binding to 14-3-3 proteins. Mutations in the 14-3-3-binding motif in USP8 are related to Cushing's disease. However, the molecular basis of USP8 activity regulation remains unclear. This study identified amino acids 645-684 of USP8 as an autoinhibitory region, which might interact with the catalytic USP domain, as per the results of pull-down and single-molecule FRET assays performed in this study. In silico modelling indicated that the region forms a WW-like domain structure, plugs the catalytic cleft, and narrows the entrance to the ubiquitin-binding pocket. Furthermore, 14-3-3 inhibited USP8 activity partly by enhancing the interaction between the WW-like and USP domains. These findings provide the molecular basis of USP8 autoinhibition via the WW-like domain. Moreover, they suggest that the release of autoinhibition may underlie Cushing's disease due to USP8 mutations. In order to advance our understanding of the regulation of Ubiquitin-specific protease 8 (USP8), which is known to play a role in Cushing's Disease, Kakihara et al identify and characterise amino acids 645-684 of USP8, which serve as an autoinhibitory region. Their pull-down and single-molecule FRET analysis, as well as in silico modelling, suggest that the release of USP8 autoinhibition may underlie Cushing's disease.
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