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Journal Article

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

MPS-Authors
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Qiao,  S.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Lee,  C.-W.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons238966

Sherpa,  D.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Chrustowicz,  J.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Duennebacke,  M.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Steigenberger,  B.
Scientific Service Groups, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213408

Karayel,  O.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Tung Vu,  Duc
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Gronau,  Susanne von
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons78356

Mann,  M.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons172944

Wilfling,  F.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

/persons/resource/persons213292

Schulman,  Brenda
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Qiao, S., Lee, C.-W., Sherpa, D., Chrustowicz, J., Cheng, J. D., 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(1): 3041. doi:10.1038/s41467-022-30803-9.


Cite as: https://hdl.handle.net/21.11116/0000-000A-A3BA-C
Abstract
The GID E3 ligase regulates glucose-induced degradation in yeast, and key physiology. This study unveils E3 ligase regulation by reshaping the substrate binding site, blocking substrate access to ubiquitination active sites, and a Cage-like assembly. 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.