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

Qiao, Shuai; Lee, Chia-Wei; Sherpa, Dawafuti; Chrustowicz, Jakub; Cheng, Jingdong; Duennebacke, Maximilian; Steigenberger, Barbara; Karayel, Ozge; Vu, Duc Tung; von Gronau, Susanne; Mann, Matthias; Wilfling, Florian; Schulman, Brenda A.

doi:10.1038/s41467-022-30803-9

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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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引用

Qiao, S., Lee, C.-W., Sherpa, D., Chrustowicz, J., Cheng, J., Duennebacke, M., Steigenberger, B., Karayel, O., Vu, D. T., von Gronau, S., Mann, M., Wilfling, F., & Schulman, B. A. (2022). Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation. Nature Communications, 13:. doi:10.1038/s41467-022-30803-9.

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

要旨

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.