Identification of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor.
The VHL protein (pVHL) is a component of an E3 ubiquitin ligase complex which is involved in the ubiquitination and degradation of the alpha subunits of HIF (hypoxia-inducible factor) in the presence of oxygen. However, it is of considerable interest to identify pVHL substrates other than HIF. In our previous ... studies, we have shown that VDU1 (pVHL-interacting deubiquitinating enzyme-1) can be ubiquitinated for rapid degradation in a pVHL-dependent manner. In this report we show that another uncharacterized deubiquitinating enzyme, named VDU2 (pVHL-interacting deubiquitinating enzyme-2), is a substrate of pVHL. Based on human and mouse cDNA sequences, VDU1 and VDU2 are identical in approximately 59% of the amino acids with strong homology in the N-terminus and C-terminus and a weaker similarity in the middle region. VDU2 contains the signature motifs of the ubiquitin-specific processing protease family and possesses deubiquitinating activity. Like VDU1, VDU2 interacts with pVHL beta-domain and these two proteins can compete with each other to bind to pVHL. Finally, we demonstrate that VDU2 can also be ubiquitinated and degraded in a pVHL-dependent manner. Based on their amino acid sequence homology and functional interaction with pVHL, VDU1 and VDU2 define a subfamily of ubiquitin specific processing proteases. Since deubiquitination, by reversing ubiquitination, has been recognized as an important regulatory step in ubiquitination-related processes, VDU1 and VDU2 could be important substrates of pVHL E3 ligase complex.
Mesh Terms:
Amino Acid Sequence, Animals, COS Cells, Catalysis, Dose-Response Relationship, Drug, Endopeptidases, Humans, Ligases, Molecular Sequence Data, Plasmids, Sequence Alignment, Substrate Specificity, Transfection, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Amino Acid Sequence, Animals, COS Cells, Catalysis, Dose-Response Relationship, Drug, Endopeptidases, Humans, Ligases, Molecular Sequence Data, Plasmids, Sequence Alignment, Substrate Specificity, Transfection, Tumor Suppressor Proteins, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, von Hippel-Lindau Disease
Biochem. Biophys. Res. Commun.
Date: Jun. 14, 2002
PubMed ID: 12056827
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