Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control
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.
Authors
- Julian F. Ehrmann (ORCID: https://orcid.org/0000-0003-2518-5681)
- Luiza Deszcz (ORCID: https://orcid.org/0000-0001-5004-3584)
- R Kurzbauer
- Ramanujan S. Hegde (ORCID: https://orcid.org/0000-0001-8338-852X)
- Paul V. Murphy (ORCID: https://orcid.org/0000-0002-1529-6540)
- Jana Neuhold
- Alexandra Shulkina (ORCID: https://orcid.org/0009-0008-4266-2789)
- Daniel B. Grabarczyk (ORCID: https://orcid.org/0000-0003-0216-7085)
- Gijs A. Versteeg (ORCID: https://orcid.org/0000-0002-6150-2165)
- Juyeon Lee
- Anton Meinhart (ORCID: https://orcid.org/0000-0002-0707-5860)
- Woo Seok Yang (ORCID: https://orcid.org/0000-0002-0022-0295)
- Eszter Zavodszky (ORCID: https://orcid.org/0000-0002-4123-8758)
- Hyun Kyu Song (ORCID: https://orcid.org/0000-0001-5684-4059)
- Alexander Schleiffer (ORCID: https://orcid.org/0000-0001-6251-2747)
- Tim Clausen (ORCID: https://orcid.org/0000-0003-1582-6924)
- Jin Seok Shin (ORCID: https://orcid.org/0000-0002-3617-7954)
- Lillie Bell
Institutions
- University of Vienna (AT)
- MRC Laboratory of Molecular Biology (GB)
- Research Institute of Molecular Pathology (AT)
- Korea University (KR)
- Max Perutz Labs (AT)
- Vienna Biocenter (AT)
- Vienna BioCenter Core Facilities (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Science
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1126/science.adv9309
- Citations
- 9
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 7.25