ArticleScience (New York, N.Y.)2025
Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control.
Article in Science (New York, N.Y.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed.
- The Tianshan Mountains as a biogeographic barrier driving North-South divergence and local adaptation inPlant diversity · 2026Article
- Survey of the human proteostasis network: the ubiquitin-proteasome system.bioRxiv : the preprint server for biology · 2026Article
- Mitochondrial presequences are more than just address labels.Protein science : a publication of the Protein Society · 2026Review
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Degrons and degradation signals beyond short linear motifs.Nature chemical biology · 2026Review
- Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity.Nature communications · 2026Article
- The generation and consequences of N-terminal proteoform diversity.Cell reports · 2025Review
- Article
- Mechanism of chaperone recruitment and retention on mitochondrial precursors.Molecular biology of the cell · 2025Article
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Eukaryotic cells have evolved sophisticated quality control mechanisms to eliminate aggregation-prone proteins that compromise cellular health. Central to this defense is the ubiquitin-proteasome system, where UBR4 acts as an essential E4 ubiquitin ligase, amplifying degradation marks on defective proteins. Cryo-electron microscopy analysis of UBR4 in complex with its cofactors KCMF1 and CALM1 reveals a massive 1.3-megadalton ring structure, featuring a central substrate-binding arena and flexibly attached catalytic units. Our structure shows how UBR4 binds substrate and extends lysine-48-specific ubiquitin chains. Efficient substrate targeting depends on both preubiquitination and specific N-degrons, with KCMF1 acting as a key substrate filter. The architecture of the E4 megacomplex is conserved across eukaryotes, but species-specific adaptations allow UBR4 to perform its precisely tuned quality control function in diverse cellular environments.
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Registered trials
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