Topic
CUL4A
About: CUL4A is a research topic. Over the lifetime, 180 publications have been published within this topic receiving 11635 citations. The topic is also known as: cullin 4A.
Papers published on a yearly basis
Papers
TL;DR: A basis for thalidomide teratogenicity is revealed and may contribute to the development of new thalidmide derivatives without teratogenic activity.
Abstract: Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.
1,925 citations
TL;DR: The structural mechanisms and molecular logic underlying the assembly and versatility of a new family of cullin-RING E3 complexes are revealed and a novel family of WD40-repeat proteins are identified.
Abstract: Protein ubiquitination is a common form of post-translational modification that regulates a broad spectrum of protein substrates in diverse cellular pathways1 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 complexes2,3 Conserved from yeast to human, the DDB1–CUL4–ROC1 complex is a recently identified cullin-RING ubiquitin ligase, which regulates DNA repair4,5,6,7,8,9,10, DNA replication11,12,13,14 and transcription15, and can also be subverted by pathogenic viruses to benefit viral infection16 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 β-propeller domain for cullin scaffold binding and a variably attached separate double-β-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
662 citations
TL;DR: The CUL4-DDB1 ubiquitin ligase regulates cell proliferation, survival, DNA repair, and genomic integrity through targeted ubiquitination of key regulators, yet the substrate receptors that dictate the specificity of this ubiquitinations machinery have been largely unknown.
444 citations
TL;DR: The studies suggest that CUL4–DDB1 ligases use WDR proteins as molecular adaptors for substrate recognition, and modulate multiple biological processes through ubiquitin-dependent proteolysis.
Abstract: CUL4–DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation
426 citations
TL;DR: The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways.
400 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 9 |
| 2020 | 13 |
| 2019 | 11 |
| 2018 | 8 |
| 2017 | 9 |
| 2016 | 9 |