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Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery.

Nature | Oct 5, 2006

Protein ubiquitination is a common form of post-translational modification that regulates a broad spectrum of protein substrates in diverse cellular pathways. Through a three-enzyme (E1-E2-E3) cascade, the attachment of ubiquitin to proteins is catalysed by the E3 ubiquitin ligase, which is best represented by the superfamily of the cullin-RING complexes. Conserved from yeast to human, the DDB1-CUL4-ROC1 complex is a recently identified cullin-RING ubiquitin ligase, which regulates DNA repair, DNA replication and transcription, and can also be subverted by pathogenic viruses to benefit viral infection. Lacking a canonical SKP1-like cullin adaptor and a defined substrate recruitment module, how the DDB1-CUL4-ROC1 E3 apparatus is assembled for ubiquitinating various substrates remains unclear. Here we present crystallographic analyses of the virally hijacked form of the human DDB1-CUL4A-ROC1 machinery, which show that DDB1 uses one beta-propeller domain for cullin scaffold binding and a variably attached separate double-beta-propeller fold for substrate presentation. Through tandem-affinity purification of human DDB1 and CUL4A complexes followed by mass spectrometry analysis, we then identify a novel family of WD40-repeat proteins, which directly bind to the double-propeller fold of DDB1 and serve as the substrate-recruiting module of the E3. Together, our structural and proteomic results reveal the structural mechanisms and molecular logic underlying the assembly and versatility of a new family of cullin-RING E3 complexes.

Pubmed ID: 16964240 RIS Download

Mesh terms: Amino Acid Motifs | Amino Acid Sequence | Binding Sites | Carrier Proteins | Crystallography, X-Ray | Cullin Proteins | DNA-Binding Proteins | Humans | Models, Molecular | Molecular Sequence Data | Pliability | Protein Binding | Protein Structure, Quaternary | Proteomics | Structure-Activity Relationship | Substrate Specificity | Ubiquitin | Ubiquitin-Protein Ligases

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Mouse Genome Informatics (Data, Gene Annotation)

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