SCFCdc4like

SCFCdc4like refers to a class of SKP1-CUL1-F-box (SCF) ubiquitin ligase complexes in which the substrate receptor is a Cdc4-like F-box protein. In these assemblies, the F-box protein provides substrate specificity by binding phosphorylated degrons, while Skp1 links the receptor to Cullin-1 and the RING protein ROC1 to complete the ligase. Cdc4-like proteins are characterized by F-box motifs that recruit Skp1 and by Cdc4-family substrate-binding domains, typically WD40 repeats, which recognize phosphodegron motifs on target proteins.

Function and mechanism

SCFCdc4like complexes catalyze ubiquitination of specific substrates, marking them for degradation by the proteasome. Substrate recognition usually depends on phosphorylation by upstream kinases, creating degron signals that the WD40 domain of the Cdc4-like receptor can bind. This regulated degradation controls diverse cellular processes, including cell cycle progression, differentiation, and signal transduction. The activity of SCFCdc4like ligases is modulated by post-translational modifications of Cullin-1, such as neddylation, which enhances ubiquitin transfer.

Notable components and substrates

In humans, the best-characterized Cdc4-like F-box protein is FBXW7, which forms SCF complexes that target several oncoproteins for destruction. Prominent substrates include Cyclin E, c-Myc, and the Notch intracellular domain, among others. Yeast and other organisms possess CDC4-like receptors that regulate substrates critical for cell cycle control, such as Sic1 in budding yeast. The specific spectrum of substrates can vary across species and cell types.

Clinical and research relevance

Mutations or loss of Cdc4-like F-box proteins, especially FBXW7, are associated with cancer and developmental disorders due to stabilization of oncogenic substrates. Studying SCFCdc4like ligases provides insight into ubiquitin-mediated proteostasis and offers potential avenues for therapeutic intervention that modulate substrate degradation.