ArticleProceedings of the National Academy of Sciences of the United States of America2025
Structural insights into the ubiquitin-independent midnolin-proteasome pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Survey of the human proteostasis network: the ubiquitin-proteasome system.bioRxiv : the preprint server for biology · 2026Article
- Structural dynamics of the midnolin-proteasome during ubiquitin-independent substrate turnover.Nature communications · 2026Article
- Proteasomal control of transcription factors: mechanisms, regulation and dysregulation.Cellular and molecular life sciences : CMLS · 2026Review
- Emerging roles of Midnolin in Cancer, Parkinson's Disease, and Metabolic dysfunction.Molecular biology reports · 2025Review
- Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.Molecular cell · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
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 α-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 α-helix must bind to the proteasome for MIDN to stimulate proteasome activity.
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Registered trials
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