9JNI

KCMF1 Zn-coordinating domains with RCKG peptide (Sulfonic Cysteine)

Summary for 9JNI

• Entry DOI: 10.2210/pdb9jni/pdb
• Descriptor: E3 ubiquitin-protein ligase KCMF1, ARG-OCS-LYS-GLY, ZINC ION, ... (4 entities in total)
• Functional Keywords: complex, zz-domain, c2h2 zn-finger domain, kcmf1, arg/n-degon pathway, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 14313.31

Authors

Yang, W.S.,Shin, J.S.,Song, H.K. (deposition date: 2024-09-23, release date: 2025-08-27, Last modification date: 2025-09-10)

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

X-RAY DIFFRACTION (1.92 Å)