Cadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs

The F-box domain is a highly conserved structural motif that defines the largest class of ubiquitin ligases, Skp1/Cullin1/F-box protein (SCF) complexes. The only known function of the F-box motif is to form the protein interaction surface with Skp1. Here we show that the F-box domain can function as an environmental sensor. We demonstrate that the F-box domain of Met30 is a cadmium sensor that blocks the activity of the SCF Met30 ubiquitin ligase during cadmium stress. Several highly conserved cysteine residues within the Met30 F-box contribute to binding of cadmium with a K D of 8 µM. Binding induces a conformational change that allows for Met30 autoubiquitylation, which in turn leads to recruitment of the segregase Cdc48/p97/VCP followed by active SCF Met30 disassembly. The resulting inactivation of SCF Met30 protects cells from cadmium stress. Our results show that F-box domains participate in regulation of SCF ligases beyond formation of the Skp1 binding interface. The F-box domain is a conserved structural motif in ubiquitin ligases known only to bind Skp1. Here, the authors show the F-box domain is also an environmental cadmium sensor that changes conformation upon binding to disassemble the active ligase, protecting the cell from cadmium stress.