Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control

• 成果类型: Article
• 署名作者: Grabarczyk, Daniel B.; Ehrmann, Julian F.; Murphy, Paul; Yang, Woo Seok; Kurzbauer, Robert; Bell, Lillie E.; Deszcz, Luiza; Neuhold, Jana; Schleiffer, Alexander; Shulkina, Alexandra; Lee, Juyeon; Shin, Jin Seok; Meinhart, Anton; Versteeg, Gijs A.; Zavodszky, Eszter; Song, Hyun Kyu; Hegde, Ramanujan S.; Clausen, Tim
• 署名单位: Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Vienna Biocenter (VBC); Medical University of Vienna; University of Vienna; Vienna Biocenter (VBC); Medical University of Vienna; Korea University; Vienna Biocenter (VBC); Medical University of Vienna; University of Vienna; Vienna Biocenter (VBC); Max F. Perutz Laboratories (MFPL); University of Vienna; MRC Laboratory Molecular Biology; Medical University of Vienna; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9718
• DOI: 10.1126/science.adv9309
• 发表日期: 2025-08-28
• 页码: 909-914
• 关键词: cryo-em; n-recognin; ubiquitin; mechanism; survival

摘要

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.