7Z8B

Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation

Summary for 7Z8B

• Entry DOI: 10.2210/pdb7z8b/pdb
• EMDB information: 14547
• Descriptor: Cullin-7, F-box/WD repeat-containing protein 8, E3 ubiquitin-protein ligase RBX1, ... (5 entities in total)
• Functional Keywords: cullin-ring ubiquitin e3 ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 290359.38

Authors

Hopf, L.V.M.,Schulman, B.A. (deposition date: 2022-03-17, release date: 2022-08-24, Last modification date: 2024-07-24)

Primary citation

Hopf, L.V.M.,Baek, K.,Klugel, M.,von Gronau, S.,Xiong, Y.,Schulman, B.A.
Structure of CRL7 FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation.
Nat.Struct.Mol.Biol., 29:854-862, 2022

PubMed Abstract: Most cullin-RING ubiquitin ligases (CRLs) form homologous assemblies between a neddylated cullin-RING catalytic module and a variable substrate-binding receptor (for example, an F-box protein). However, the vertebrate-specific CRL7 is of interest because it eludes existing models, yet its constituent cullin CUL7 and F-box protein FBXW8 are essential for development, and CUL7 mutations cause 3M syndrome. In this study, cryo-EM and biochemical analyses reveal the CRL7 assembly. CUL7's exclusivity for FBXW8 among all F-box proteins is explained by its unique F-box-independent binding mode. In CRL7, the RBX1 (also known as ROC1) RING domain is constrained in an orientation incompatible with binding E2~NEDD8 or E2~ubiquitin intermediates. Accordingly, purified recombinant CRL7 lacks auto-neddylation and ubiquitination activities. Instead, our data indicate that CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination. The structure reveals a distinctive CRL-CRL partnership, and provides a framework for understanding CUL7 assemblies safeguarding human health.

PubMed: 35982156
DOI: 10.1038/s41594-022-00815-6

Experimental method

ELECTRON MICROSCOPY (2.8 Å)