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GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

ABSTRACT: How are E3 ubiquitin ligases configured to match substrate quaternary structures? Here, by studying the yeast GID complex, mutation of which is Glucose-Induced Degradation 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-GIDSR4 assembly 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

TISSUE(S): Cell Culture

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD024462 | Pride | 2021-04-28

REPOSITORIES: Pride

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			Action	DRS
	20191017_QX4_OzKa_SA_GID7_proteome_19.raw	Raw
	20191017_QX4_OzKa_SA_GID7_proteome_20.raw	Raw
	20191017_QX4_OzKa_SA_GID7_proteome_21.raw	Raw
	20191017_QX4_OzKa_SA_GID7_proteome_22.raw	Raw
	20191017_QX4_OzKa_SA_GID7_proteome_23.raw	Raw

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