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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta
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Functional Characterization of RING-Type E3 Ubiquitin Ligases In Vitro and In Planta

Published on: December 5, 2019

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WW domain-mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex

Weiyi Yao1, Zelin Shan1, Aihong Gu1

  • 1From the Department of Neurosurgery, Huashan Hospital, Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China and.

The Journal of Biological Chemistry
|September 15, 2018
PubMed

Insights

The Nedd4 family E3 ligases, Itch and WWP1/2, are regulated by autoinhibition. The Drosophila ortholog, Suppressor of Deltex (Su(dx)), uses a similar mechanism, with activation by dNdfip leading to Notch ubiquitination.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Nedd4 family E3 ligases, including Itch and WWP1/2, are vital for cell cycle and apoptosis, and linked to cancer.
  • Their activity is regulated by intramolecular HECT domain sequestration.
  • This autoinhibitory mechanism is conserved across species.

Purpose of the Study:

  • To investigate the autoinhibitory mechanism of Suppressor of Deltex (Su(dx)), the Drosophila ortholog of Itch and WWP1/2.
  • To understand how Su(dx) is activated and regulates its substrates, such as Notch.

Main Methods:

  • Biochemical assays to study protein interactions.
  • Analysis of Su(dx) structure and function.
  • Investigation of substrate ubiquitination.

Main Results:

  • Su(dx) exists in an inactive state due to interaction between its WW domain region and HECT domain.
  • The linker and WW2 domains are essential for regulating Su(dx) HECT activity.
  • dNdfip binding to Su(dx) WW domains releases inhibition, enabling substrate ubiquitination.
  • Notch was identified as a substrate, undergoing ubiquitination mediated by dNdfip-Su(dx).

Conclusions:

  • A conserved autoinhibitory mechanism regulates Nedd4 family E3 ligases.
  • dNdfip-Su(dx) mediates Notch ubiquitination, suggesting a role in Notch pathway regulation.
  • This highlights a dual regulatory mechanism for Notch degradation.
Keywords:
E3 ubiquitin ligaseNotch proteinSu(dx)adaptor proteinautoinhibitiondNdfipprotein degradationubiquitylation (ubiquitination)

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