1. Interaction of Hepatitis B Virus X Protein with Damaged DNA-Binding Protein p127: Structural Analysis and Identification of Antagonists.
- Author
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Bergametti, Françoise, Bianchi, Julie, and Transy, Catherine
- Subjects
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HEPATITIS B virus , *PROTEINS , *DNA-binding proteins , *ULTRAVIOLET radiation , *GENETIC mutation - Abstract
The hepatitis B virus X protein is a multifunctional protein that is essential for natural infection and has also been implicated in liver cancer development. Previous studies have identified the DDB1 subunit of the damaged-DNA binding complex as a critical partner of X protein in the infection process, X-mediated cytotoxicity and stability of the viral protein. Here, we investigated the structural and functional constraints of X-DDB1 interaction using various mutational analyses. Our data show that the interaction interface of X with DDB1 is confined to a 15-residue epitope. All substitutions responsible for loss of binding mapped to this core-binding domain. In contrast, a marked increase in affinity for DDB1 resulted from substitutions at clustered positions lying close to the DDB1-binding epitope and correlated with loss of apoptotic potential. Selection of mutations in DDB1 that partially rescue the binding defect of an X mutant gave further insight into the contacts established between the two proteins. Importantly, both the core-binding domain of X and the gain-of-affinity X mutants inhibited DDB1- mediated stabilization of wild-type X protein. These X protein derivatives thus provide the basis for the development of therapeutic agents that antagonize X function through competitive inhibition of X-DDB1 interaction.Copyright © 2002 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2002
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