Skp1Cul1Fbox

Skp1-Cullin-1-F-box (Skp1-CUL1-F-box) complexes, commonly known as SCF ubiquitin ligases, are a major class of multi-subunit E3 ubiquitin ligases in eukaryotes. They regulate the ubiquitination and subsequent proteasomal degradation of specific target proteins, thereby controlling a wide range of cellular processes.

The core SCF architecture includes the scaffold protein Cullin-1 (CUL1), the adaptor Skp1, and the RING-finger protein RBX1 (Roc1), which recruits the ubiquitin-conjugating enzyme (E2). The F-box protein serves as the substrate receptor, binding Skp1 through an F-box motif and recognizing degron motifs in substrates via its C-terminal substrate-binding domain. A large family of F-box proteins exists (including FBXW, FBXL, and FBXO subfamilies), providing substrate specificity to the complex.

SCF ligase activity is regulated by post-translational modification: neddylation of CUL1 by NEDD8 activates the complex and promotes ubiquitin transfer, while deneddylation by the COP9 signalosome (CSN) downregulates activity. Substrates are typically polyubiquitinated with Lys48-linked chains, targeting them for degradation by the 26S proteasome; alternative ubiquitin linkages can signal other cellular outcomes in some cases.

SCF complexes influence numerous biological processes, including cell cycle progression, DNA replication licensing, transcription factor turnover, and responses to signaling pathways. The repertoire of F-box proteins enables context-dependent substrate selection, contributing to tissue- and condition-specific regulation of protein stability. Misregulation of SCF components has been associated with diseases such as cancer, highlighting their critical role in cellular homeostasis. As modular E3 ligases, SCF complexes exemplify how protein degradation is tailored through combinatorial subunit composition.