Structural insights into the interaction between testis-specific Y-encoded-like protein 5 and ubiquitin-specific protease 7
(2025) Protein Science — Vol. 34, n° 5, p. e70116 (2025)
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- The Alternative Lengthening of Telomeres (ALT) mechanism enables telomere maintenance, contributing to the immortality of certain cancer cells. Disrupting the interaction between testis-specific Y-encoded-like protein 5 (TSPYL5) and ubiquitin-specific protease 7 (USP7) has emerged as a promising strategy to target ALT-dependent cancers. While the N-terminal MATH domain of USP7 mediates the protein interaction, the regions of TSPYL5 involved in binding remain unclear. Here, we present a structural analysis of the TSPYL5-USP7 interaction to guide targeted therapeutic strategies. We showed that TSPYL5 is intrinsically disordered, with an unfolded N-terminal region and partial structure in the C-terminal half. In vitro, recombinantly expressed TSPYL5 binds USP7 with nanomolar affinity and is prone to C-terminal truncation. However, the truncated form retained a similar binding affinity for USP7, suggesting the primary interaction site resides in the N-terminal region of TSPYL5. We identified three key binding hotspots within TSPYL5: residues 65-97, residues 210-262, and residues 368-388. Moreover, TSPYL5 forms trimers that further assemble into hexamers. This study provides the first structural and quantitative analysis of the TSPYL5-USP7 interaction, highlighting these three binding sites. These findings lay the groundwork for the development of novel inhibitors targeting ALT-dependent cancers.
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Ancia, M., Wahni, K., Chakrowf, J., El Aakchioui, A., Claude, E., de Lhoneux, G., Liberelle, M., Janvier, S., Baranova, E., Malo Pueyo, J., Jijon Vergara, A., Papadopoulos, N., Balty, C., Dejeu, J., Decottignies, A., Messens, J., & Frédérick, R. (2025). Structural insights into the interaction between testis-specific Y-encoded-like protein 5 and ubiquitin-specific protease 7. Protein Science, 34(5), e70116. https://doi.org/10.1002/pro.70116 (Original work published 2025)