The F-box: a new motif for ubiquitin dependent proteolysis in cell cycle regulation and signal transduction

The ubiquitin system of intracellular protein degradation controls the abun dance of many critical regulatory proteins. Specificity in the ubiquitin sy stem is determined largely at the level of substrate recognition, a step th at is mediated by E3 ubiquitin ligases. Analysis of the mechanisms of phosp horylation directed proteolysis in cell cycle regulation has uncovered a ne w class of E3 ubiquitin ligases called SCF complexes, which are composed of the subunits Skp1, Rbx1, Cdc53 and any one of a large number of different F-box proteins. The substrate specificity of SCF complexes is determined by the interchangeable F-box protein subunit, which recruits a specific set o f substrates for ubiquitination to the core complex composed of Skp1, Rbx1, Cdc53 and the E2 enzyme Cdc34. F-box proteins have a bipartite structure - the shared F-box motif links F-box proteins to Skp1 and the core complex, whereas divergent protein-protein interaction motifs selectively bind their cognate substrates, To date all known SCF substrates are recognised in a s trictly phosphorylation dependent manner, thus linking intracellular signal ling networks to the ubiquitin system. The plethora of different F-box prot eins in databases suggests that many pathways will be governed by SCF-depen dent proteolysis. Indeed, genetic analysis has uncovered roles for F-box pr oteins in a variety of signalling pathways, ranging from nutrient sensing i n yeast to conserved developmental pathways in plants and animals. Moreover , structural analysis has revealed ancestral relationships between SCF comp lexes and two other E3 ubiquitin ligases, suggesting that the combinatorial use of substrate specific adaptor proteins has evolved to allow the regula tion of many cellular processes. Here, we review the known signalling pathw ays that are regulated by SCF complexes and highlight current issues in pho sphorylation dependent protein degradation. (C) 1999 Elsevier Science Ltd. All rights reserved.