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

Author

Listed:
  • Shuai Qiao

    (Max Planck Institute of Biochemistry
    Zhejiang University School of Medicine)

  • Chia-Wei Lee

    (Max Planck Institute of Biochemistry
    Max Planck Institute of Biochemistry
    Harvard T.H. Chan School of Public Health)

  • 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
    Max Planck Institute of Biophysics)

  • Brenda A. Schulman

    (Max Planck Institute of Biochemistry)

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.

Suggested Citation

  • Shuai Qiao & Chia-Wei Lee & Dawafuti Sherpa & Jakub Chrustowicz & Jingdong Cheng & Maximilian Duennebacke & Barbara Steigenberger & Ozge Karayel & Duc Tung Vu & Susanne Gronau & Matthias Mann & Floria, 2022. "Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30803-9
    DOI: 10.1038/s41467-022-30803-9
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    Cited by:

    1. Philip Barbulescu & Chetan K. Chana & Matthew K. Wong & Ines Ben Makhlouf & Jeffrey P. Bruce & Yuqing Feng & Alexander F. A. Keszei & Cassandra Wong & Rukshana Mohamad-Ramshan & Laura C. McGary & Moha, 2024. "FAM72A degrades UNG2 through the GID/CTLH complex to promote mutagenic repair during antibody maturation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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