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Detection of Protein Ubiquitination
Published on: August 19, 2009
UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover
Gabriela Alexandru1, Johannes Graumann, Geoffrey T Smith
1Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
Cell
|September 9, 2008
Summary
The protein p97 (also known as VCP) is crucial for protein degradation. New research reveals p97 interacts with numerous ubiquitin ligases, suggesting a wider role in regulating protein turnover.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- p97 (also known as VCP) is an ATP-dependent chaperone involved in endoplasmic reticulum-associated degradation.
- Its role in soluble protein turnover is less understood, with substrate binding mediated by cofactors containing ubiquitin-binding domains.
Purpose of the Study:
- To investigate the interactions of p97 with UBX-domain proteins and associated E3 ubiquitin ligases.
- To elucidate the role of p97 in the turnover of soluble proteins, specifically focusing on hypoxia-inducible factor 1alpha (HIF1alpha).
Main Methods:
- Network proteomics was employed to identify protein-protein interactions.
- Ubiquitin-binding domains and E3 ubiquitin ligases associated with p97 and UBX proteins were analyzed.
- Depletion of p97 was performed to assess its effect on HIF1alpha levels.
Main Results:
- p97 was found to assemble with all 13 mammalian UBX-domain proteins.
- UBX proteins interact with numerous E3 ubiquitin ligases, expanding the known interactome of p97.
- UBXD7 was identified as a linker between p97, the CUL2/VHL ubiquitin ligase, and its substrate HIF1alpha.
- Depletion of p97 resulted in HIF1alpha accumulation and increased expression of a HIF1alpha target gene.
Conclusions:
- p97, through its interaction with UBX proteins, engages with a wide array of E3 ubiquitin ligases.
- This suggests p97 plays a more extensive role in the global regulation of protein turnover than previously recognized.
- The p97-UBXD7-CUL2/VHL axis is critical for HIF1alpha degradation.
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