FboxWD40repeat

FboxWD40repeat is a class of eukaryotic proteins characterized by the combination of an F-box motif and WD40 repeats. The F-box domain mediates binding to SKP1, linking the protein to the Skp1-CUL1-F-box (SCF) ubiquitin ligase complex. The WD40 repeats form a beta-propeller scaffold that enables specific protein–protein interactions, providing the recognition surface for substrates. Together, these features allow FboxWD40repeat proteins to act as substrate receptors within SCF E3 ubiquitin ligases, directing ubiquitination and often proteasomal degradation of target proteins.

In most organisms, these proteins belong to the FBXW family, which comprises F-box and WD40-repeat-containing proteins, although other F-box subclasses may carry WD40 repeats as well. In humans, well-characterized members include FBXW7 (Cdc4), which targets cyclin E, Myc, and other regulators, and β-TrCP1/2 (BTRC/FBXW11), which recognize substrates such as IκBα and β-catenin. These factors influence cell cycle control, signal transduction, and transcriptional regulation by modulating the stability of key regulatory proteins.

Functional diversity arises from variation in WD40-repeat number and substrate-binding surfaces, enabling a wide range of substrates and biological processes. The evolution of FboxWD40repeat proteins is marked by expansion in multicellular eukaryotes, reflecting the need to regulate diverse signaling pathways and developmental programs.

Research staying power: FboxWD40repeat proteins are investigated for their roles in development, cancer, immunity, and proteostasis, and are used to study protein interaction networks and the specificity determinants of SCF-mediated ubiquitination.