Mechanisms and function of substrate recruitment by F-box proteins

Through their role as substrate adaptors for S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) ubiquitin ligase complexes, F-box proteins control the degradation of a large number of proteins with wide-ranging functions. Studying the mechanisms of substrate recruitment by F-box proteins has increased our understanding of their dysregulation in disease and might lead to targeted therapies. S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins as substrate adaptors to mediate the degradation of a large number of regulatory proteins involved in diverse processes. The dysregulation of SCF complexes and their substrates contributes to multiple pathologies. In the 14 years since the identification and annotation of the F-box protein family, the continued identification and characterization of novel substrates has greatly expanded our knowledge of the regulation of substrate targeting and the roles of F-box proteins in biological processes. Here, we focus on the evolution of our understanding of substrate recruitment by F-box proteins, the dysregulation of substrate recruitment in disease and potential avenues for F-box protein-directed disease therapies.