Skp1cullinFbox

Skp1CullinFbox refers to the Skp1-Cullin-F-box protein complex, a class of cullin-RING E3 ubiquitin ligases (CRLs) that catalyze ubiquitination of specific substrate proteins. The core assembly comprises three components: the adaptor protein Skp1, the scaffold protein Cullin-1, and the RING finger protein Rbx1 that recruits the ubiquitin-conjugating enzyme UBE2D/UBE2R. The variable substrate receptor is an F-box protein, which binds Skp1 via its F-box motif and recognizes specific degron motifs on substrates. The resulting complex functions by bringing the substrate in proximity to the E2 enzyme to catalyze transfer of ubiquitin, often forming polyubiquitin chains that target the substrate to the 26S proteasome for degradation.

Activity is modulated by neddylation of Cullin by NEDD8, which enhances ligase activity; deneddylation by the COP9 signalosome reduces activity. Complex assembly is regulated during the cell cycle and by post-translational modifications. The F-box protein determines substrate specificity, allowing a single SCF core to regulate many substrates.

SCF complexes regulate diverse processes, including cell cycle transitions (e.g., degradation of cyclins and CDK inhibitors), transcriptional control, DNA replication, and signal transduction. Dysregulation of SCF activity or F-box proteins is linked to cancer and developmental disorders. Moreover, as selective degraders of pathogenic proteins, SCF-based mechanisms inspire approaches such as PROTACs and molecular glues in targeted protein degradation.

In evolutionary terms, the SCF type of CRLs is conserved across eukaryotes, with humans encoding dozens of F-box proteins that expand substrate repertoire. Variants with different Cullins (CUL1, CUL2, CUL3, etc.) form related CRLs.