GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme
Copyright policy )GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme
SUMMARYTo achieve precise cellular regulation, E3 ubiquitin ligases must be configured to match substrate quaternary structures. Here, by studying the yeast GID complex, mutation of which isGlucose-InducedDegradation deficient, we discover supramolecular chelate assembly as an E3 ligase strategy for targeting an oligomeric substrate. Cryo EM structures show that to bind the tetrameric substrate fructose-1,6-bisphosphatase (Fbp1), two otherwise functional GID E3s assemble into a 20-protein Chelator-GIDSR4, which resembles an organometallic supramolecular chelate. The Chelator-GIDSR4assembly avidly binds multiple Fbp1 degrons and positions Fbp1 so that its protomers are simultaneously ubiquitylated at lysines near its allosteric and substrate binding sites. Significantly, key structural and biochemical features -including capacity for supramolecular assembly - are preserved in the human ortholog, the CTLH E3. Based on our integrative structural, biochemical and cell biological data, we propose that higher-order E3 ligase assembly generally underlies multipronged targeting, capable of simultaneously incapacitating multiple protomers and functionalities of oligomeric substrates.
- Max Planck Institute of Biochemistry Germany
- Max Planck Institute for Biology Germany
- Max Planck Society Germany
Models, Molecular, Protein Conformation, alpha-Helical, Binding Sites, Cryoelectron Microscopy, Gluconeogenesis, Intracellular Signaling Peptides and Proteins, Gene Expression, Article, Recombinant Proteins, Fructose-Bisphosphatase, Kinetics, Multienzyme Complexes, Animals, Humans, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, K562 Cells, Promoter Regions, Genetic, Cell Adhesion Molecules, Adaptor Proteins, Signal Transducing, Protein Binding
Models, Molecular, Protein Conformation, alpha-Helical, Binding Sites, Cryoelectron Microscopy, Gluconeogenesis, Intracellular Signaling Peptides and Proteins, Gene Expression, Article, Recombinant Proteins, Fructose-Bisphosphatase, Kinetics, Multienzyme Complexes, Animals, Humans, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, K562 Cells, Promoter Regions, Genetic, Cell Adhesion Molecules, Adaptor Proteins, Signal Transducing, Protein Binding
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