Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation

• 成果类型: Article
• 署名作者: Korchak, Emilie J.; Sharafi, Mona; Maisonet, Isabella Jaen; Chaparro, Andres Salazar -; V. Semenova, Irina; Khan, Hamza; O'Neil, Alison L.; Caro, Pilar; Schaaf, Christian P.; Buhrlage, Sara J.; Bezsonova, Irina
• 署名单位: University of Connecticut; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Wesleyan University; Wesleyan University; Ruprecht Karls University Heidelberg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10514
• DOI: 10.1073/pnas.2510252122
• 发表日期: 2025-09-30
• 关键词: ubiquitin-specific protease; evolutionary conservation; substrate recognition; catalytic domain; consurf; gene; deubiquitination; identification; usp7/hausp; regulator

摘要

Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.