Structural insights into the ubiquitin- independent midnolin- proteasome pathway

• 成果类型: Article
• 署名作者: Peddada, Nagesh; Zhong, Xue; Yin, Yan; Lazaro, Danielle Renee; Wang, Jianhui; Lyon, Stephen; Choi, Jin Huk; Bai, Xiao-Chen; Moresco, Eva Marie Y.; Beutler, Bruce
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9888
• DOI: 10.1073/pnas.2505345122
• 发表日期: 2025-05-13
• 关键词: myeloma cells; inhibitors; architecture; protein

摘要

The protein midnolin (MIDN) augments proteasome activity in lymphocytes and dramatically facilitates the survival and proliferation of B-lymphoid malignancies. MIDN binds both to proteasomes and to substrates, but the mode of interaction with the proteasome is unknown, and the mechanism by which MIDN facilitates substrate degradation in a ubiquitin-independent manner is incompletely understood. Here, we present cryoelectron microscopy (cryo-EM) structures of the substrate-engaged, MIDN-bound human proteasome in two conformational states. MIDN induces proteasome conformations similarly to ubiquitinated substrates by using its ubiquitin-like domain to bind to the deubiquitinase RPN11 (PSMD14). By simultaneously binding to RPN1 (PSMD2) with its C-terminal alpha- helix, MIDN positions its substrate-carrying Catch domain above the proteasome ATPase channel through which substrates are translocated before degradation. Our findings suggest that both ubiquitin-like domain and C-terminal alpha-helix must bind to the proteasome for MIDN to stimulate proteasome activity.