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The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger, and an E2-binding site.

Efficient targeting of proteins for degradation from the secretory pathway is essential to homeostasis. This occurs through endoplasmic reticulum (ER)-associated degradation (ERAD). In this study, we establish that a human ubiquitin ligase (E3), gp78, and a specific E2, Ube2g2, are both critically important for ERAD of multiple substrates. gp78 exhibits a complex domain structure that, in addition to the RING finger, includes a ubiquitin-binding Cue domain and a specific binding site for Ube2g2. Disruption of either of these domains abolishes gp78-mediated ubiquitylation and protein degradation, resulting in accumulation of substrates in their fully glycosylated forms in the ER. This suggests that gp78-mediated ubiquitylation is an early step in ERAD that precedes dislocation of substrates from the ER. The in vivo requirement for both an E2-binding site distinct from the RING finger and a ubiquitin-binding domain intrinsic to an E3 suggests a previously unappreciated level of complexity in ubiquitin ligase function. These results also provide proof of principle that interrupting a specific E2-E3 interaction can selectively inhibit ERAD.

Pubmed ID: 16407162

Authors

  • Chen B
  • Mariano J
  • Tsai YC
  • Chan AH
  • Cohen M
  • Weissman AM

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 10, 2006

Associated Grants

  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Amino Acid Motifs
  • Binding Sites
  • Cell Line
  • Endoplasmic Reticulum
  • Humans
  • Protein Binding
  • Protein Structure, Tertiary
  • Substrate Specificity
  • Ubiquitin
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases