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

Autor: Lauinger L; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA. llauinge@uci.edu., Andronicos A; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA., Flick K; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA., Yu C; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, 92697, USA., Durairaj G; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA., Huang L; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, 92697, USA., Kaiser P; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697, USA. pkaiser@uci.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 08; Vol. 15 (1), pp. 3894. Date of Electronic Publication: 2024 May 08.
DOI: 10.1038/s41467-024-48184-6
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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