| RRC ID |
87822
|
| Author |
Yamanaka S, Nagaoka K, Shoya Y, Nishino K, Mikura Y, Tanaka K, Konishi K, Hasegawa Y, Hijikata A, Kosako H, Sawasaki T.
|
| Title |
An interactome-based framework for DDB1- and CUL4-associated factor prioritization in targeted protein degradation.
|
| Journal |
Mol Cell
|
| Abstract |
The DDB1- and CUL4-associated factor (DCAF) family functions as substrate receptors within Cullin4-really interesting new gene (RING) ubiquitin ligases (CRL4s), facilitating proteasomal degradation of targeted substrates. Although CRL4-based targeted protein degradation (TPD) has emerged as a promising strategy to modulate undruggable proteins, the complex formation, substrates, and functional properties of many DCAFs remain poorly defined. In this study, using proximity biotinylation-based interactome analysis in human HEK293T cells, we systematically annotated interactors and functional associations of individual DCAFs. Furthermore, we identified substrates of the model DCAFs COP1 and DCAF3 using proximity biotinylation coupled with multi-omics approaches. By combining biochemical and cell-based analyses, we establish CRL4 complex formation and DCAF autodegradation as experimentally tractable proxy indicators to evaluate DCAF degradation activity and propose a set of high-activity DCAFs. These datasets establish a resource for functional characterization of DCAFs and provide a framework for their prioritization in TPD.
|
| Volume |
86(7)
|
| Pages |
1397-1416.e11
|
| Published |
2026-4-2
|
| DOI |
10.1016/j.molcel.2026.03.004
|
| PII |
S1097-2765(26)00160-7
|
| PMID |
41932313
|
| MeSH |
Biotinylation
Cullin Proteins* / genetics
Cullin Proteins* / metabolism
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
HEK293 Cells
Humans
Proteasome Endopeptidase Complex / metabolism
Protein Binding
Protein Interaction Mapping / methods
Protein Interaction Maps
Proteolysis*
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism
Ubiquitination
|
| IF |
15.584
|
| Resource |
| DNA material |
pCAGGS (RDB08938)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394)
CSII-CMV-MCS-IRES2-Bsd (RDB04385) |
