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 abundance of many critical regulatory proteins. Specificity in the ubiquitin system is determined largely at the level of substrate recognition, a step that is mediated by E3 ubiquitin ligases. Analysis of the mechanisms of phosphorylation directed proteolysis in cell cycle regulation has uncovered a new 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 of 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 strictly phosphorylation dependent manner, thus linking intracellular signalling networks to the ubiquitin system. The plethora of different F-box proteins in databases suggests that many pathways will be governed by SCF-dependent proteolysis. Indeed, genetic analysis has uncovered roles for F-box proteins in a variety of signalling pathways, ranging from nutrient sensing in yeast to conserved developmental pathways in plants and animals. Moreover, structural analysis has revealed ancestral relationships between SCF complexes and two other E3 ubiquitin ligases, suggesting that the combinatorial use of substrate specific adaptor proteins has evolved to allow the regulation of many cellular processes. Here, we review the known signalling pathways that are regulated by SCF complexes and highlight current issues in phosphorylation dependent protein degradation.
Craig
K L
KL
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
Tyers
M
M
D000595:Amino Acid Sequence; D000818:Animals; D017360:Arabidopsis; D002453:Cell Cycle; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000737:chemistry*; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*
D014452:Ubiquitins; D044843:SKP Cullin F-Box Protein Ligases; D010453:Peptide Synthases