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

Linda Lauinger (), Anna Andronicos, Karin Flick, Clinton Yu, Geetha Durairaj, Lan Huang and Peter Kaiser ()
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Linda Lauinger: University of California, Irvine
Anna Andronicos: University of California, Irvine
Karin Flick: University of California, Irvine
Clinton Yu: University of California, Irvine
Geetha Durairaj: University of California, Irvine
Lan Huang: University of California, Irvine
Peter Kaiser: University of California, Irvine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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 SCFMet30 ubiquitin ligase during cadmium stress. Several highly conserved cysteine residues within the Met30 F-box contribute to binding of cadmium with a KD 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 SCFMet30 disassembly. The resulting inactivation of SCFMet30 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.

Date: 2024
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DOI: 10.1038/s41467-024-48184-6

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