Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation

Shuai Qiao, Chia-Wei Lee, Dawafuti Sherpa, Jakub Chrustowicz, Jingdong Cheng, Maximilian Duennebacke, Barbara Steigenberger, Ozge Karayel, Duc Tung Vu, Susanne Gronau, Matthias Mann, Florian Wilfling and Brenda A. Schulman ()
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Shuai Qiao: Max Planck Institute of Biochemistry
Chia-Wei Lee: Max Planck Institute of Biochemistry
Dawafuti Sherpa: Max Planck Institute of Biochemistry
Jakub Chrustowicz: Max Planck Institute of Biochemistry
Jingdong Cheng: University of Fudan
Maximilian Duennebacke: Max Planck Institute of Biochemistry
Barbara Steigenberger: Max Planck Institute of Biochemistry
Ozge Karayel: Max Planck Institute of Biochemistry
Duc Tung Vu: Max Planck Institute of Biochemistry
Susanne Gronau: Max Planck Institute of Biochemistry
Matthias Mann: Max Planck Institute of Biochemistry
Florian Wilfling: Max Planck Institute of Biochemistry
Brenda A. Schulman: Max Planck Institute of Biochemistry

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Protein degradation, a major eukaryotic response to cellular signals, is subject to numerous layers of regulation. In yeast, the evolutionarily conserved GID E3 ligase mediates glucose-induced degradation of fructose-1,6-bisphosphatase (Fbp1), malate dehydrogenase (Mdh2), and other gluconeogenic enzymes. “GID” is a collection of E3 ligase complexes; a core scaffold, RING-type catalytic core, and a supramolecular assembly module together with interchangeable substrate receptors select targets for ubiquitylation. However, knowledge of additional cellular factors directly regulating GID-type E3s remains rudimentary. Here, we structurally and biochemically characterize Gid12 as a modulator of the GID E3 ligase complex. Our collection of cryo-EM reconstructions shows that Gid12 forms an extensive interface sealing the substrate receptor Gid4 onto the scaffold, and remodeling the degron binding site. Gid12 also sterically blocks a recruited Fbp1 or Mdh2 from the ubiquitylation active sites. Our analysis of the role of Gid12 establishes principles that may more generally underlie E3 ligase regulation.

Date: 2022
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DOI: 10.1038/s41467-022-30803-9

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