The C-terminal Tail of Ubiquitin-Specific Protease 7 Facilitates Ubiquitin Release and Ensures Efficient Catalytic Turnover.

USP7 is a key ubiquitin-specific protease involved in human development. Its activity is regulated by an intramolecular interaction between the catalytic domain and the unstructured C-terminal tail. Using N TROSY and C methyl HMQC NMR spectroscopy, we show that the C-terminal peptide binds to USP7's catalytic domain only when the domain is loaded with ubiquitin. This binding triggers conformational changes in the catalytic domain, facilitating ubiquitin release and ensuring efficient catalytic turnover. These findings provide new insights into USP7 activation, which could inform therapeutic strategies for targeting USP7 in cancer and neurodevelopmental disorders.