Structural insights into the interaction between testis‐specific Y‐encoded‐like protein 5 and ubiquitin‐specific protease 7

• DOI: 10.1002/pro.70116
• Publication Date: 2025-04-22T12:14:40Z
• Authors: Marine Ancia; Khadija Wahni; Joudy Chakrowf; Asia El Aakchioui; Eloïse Claude; Guillaume de Lhoneux; Maxime Liberelle; Steven Janvier; Ekaterina Baranova; Julia Malo Pueyo; Ariana Jijon Vergara; Nicolas Papadopoulos; Clémence Balty; Jérôme Dejeu; Anabelle Decottig...; Joris Messens; Raphaël Frédérick

Abstract The Alternative Lengthening of Telomeres (ALT) mechanism enables telomere maintenance, contributing to the immortality certain cancer cells. Disrupting interaction between testis‐specific Y‐encoded‐like protein 5 (TSPYL5) and ubiquitin‐specific protease 7 (USP7) has emerged as a promising strategy target ALT‐dependent cancers. While N‐terminal MATH domain USP7 mediates interaction, regions TSPYL5 involved in binding remain unclear. Here, we present structural analysis TSPYL5–USP7 guide targeted therapeutic strategies. We showed that is intrinsically disordered, with an unfolded region partial structure C‐terminal half. In vitro , recombinantly expressed binds nanomolar affinity prone truncation. However, truncated form retained similar for USP7, suggesting primary site resides TSPYL5. identified three key hotspots within TSPYL5: residues 65–97, 210–262, 368–388. Moreover, forms trimers further assemble into hexamers. This study provides first quantitative highlighting these sites. These findings lay groundwork development novel inhibitors targeting