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

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Wilfling,  Florian       
Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany;
Research Group Mechanisms of Cellular Quality Control, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Qiao, S., Lee, C.-W., Sherpa, D., Chrustowicz, J., Cheng, J., Duennebacke, M., et al. (2022). Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation. Nature Communications, 13: 3041. doi:10.1038/s41467-022-30803-9.


Cite as: https://hdl.handle.net/21.11116/0000-000A-8E56-6
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.