9QX5

Cryo-EM structure of the C. elegans UBR4/KCMF1 complex (side focused refinement)

Summary for 9QX5

• Entry DOI: 10.2210/pdb9qx5/pdb
• EMDB information: 53435
• Descriptor: UBR-type domain-containing protein (1 entity in total)
• Functional Keywords: ubiquitin ligase, protein quality control, ligase
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 1
• Total formula weight: 488244.84

Authors

Grabarczyk, D.B.,Clausen, T. (deposition date: 2025-04-15, release date: 2025-09-03, Last modification date: 2025-10-22)

Primary citation

Grabarczyk, D.B.,Ehrmann, J.F.,Murphy, P.,Yang, W.S.,Kurzbauer, R.,Bell, L.E.,Deszcz, L.,Neuhold, J.,Schleiffer, A.,Shulkina, A.,Lee, J.,Shin, J.S.,Meinhart, A.,Versteeg, G.A.,Zavodszky, E.,Song, H.K.,Hegde, R.S.,Clausen, T.
Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control.
Science, 389:909-914, 2025

PubMed 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.

PubMed: 40875847
DOI: 10.1126/science.adv9309

Experimental method

ELECTRON MICROSCOPY (3.5 Å)