ArticleNature structural & molecular biology2022
Yeast PI31 inhibits the proteasome by a direct multisite mechanism.
Article in Nature structural & molecular biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- Pulling and gripping: Proteasomal translocation pathway elements differentially contribute to substrate unfolding.Protein science : a publication of the Protein Society · 2026Article
- Structural basis for regulation of the proteasome 20S core particle by the Parkinsonism-associated proteins FBXO7 and PI31.bioRxiv : the preprint server for biology · 2026Article
- Plasticity in the structure and assembly of proteasomes.The Journal of biological chemistry · 2026Review
- Magical moments in protease biology: proteasome autocatalytic activation and PI31-mediated inhibition.Trends in biochemical sciences · 2026Review
- Structural transitions in the stepwise assembly of proteasome core particles.Nature communications · 2026Article
- PI31 is a positive regulator of 20S immunoproteasome assembly.Journal of cell science · 2025Article
- Evidence supporting a catalytic pentad mechanism for the proteasome and other N-terminal nucleophile enzymes.Nature communications · 2025Article
- Mechanisms and regulation of substrate degradation by the 26S proteasome.Nature reviews. Molecular cell biology · 2025Review
- Proteasome: Role in T Cell Function Regulation.International journal of biological sciences · 2025Review
- Structural basis of human 20S proteasome biogenesis.Nature communications · 2024Article
- Differential Interactions of the Proteasome Inhibitor PI31 with Constitutive and Immuno-20S Proteasomes.Biochemistry · 2024Article
- Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores.Nature communications · 2022Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Proteasome inhibitors are widely used as therapeutics and research tools, and typically target one of the three active sites, each present twice in the proteasome complex. An endogeneous proteasome inhibitor, PI31, was identified 30 years ago, but its inhibitory mechanism has remained unclear. Here, we identify the mechanism of Saccharomyces cerevisiae PI31, also known as Fub1. Using cryo-electron microscopy (cryo-EM), we show that the conserved carboxy-terminal domain of Fub1 is present inside the proteasome's barrel-shaped core particle (CP), where it simultaneously interacts with all six active sites. Targeted mutations of Fub1 disrupt proteasome inhibition at one active site, while leaving the other sites unaffected. Fub1 itself evades degradation through distinct mechanisms at each active site. The gate that allows substrates to access the CP is constitutively closed, and Fub1 is enriched in mutant CPs with an abnormally open gate, suggesting that Fub1 may function to neutralize aberrant proteasomes, thereby ensuring the fidelity of proteasome-mediated protein degradation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.