Structural and antigenic variation in Hepatitis B virus oncogene, HBx.

Area of Science:

• Virology
• Structural Biology
• Evolutionary Biology

Background:

• Hepatitis B Virus (HBV) is a major cause of hepatocellular carcinoma, with the HBx protein being key to its oncogenesis.
• Previous computational studies predicted conflicting HBx protein structures, necessitating further investigation.
• Understanding HBx structure and evolution is crucial for developing targeted therapies.

Purpose of the Study:

• To compare predicted HBx protein structures from different computational methods.
• To analyze HBx structure and conservation across various HBV genotypes and host species.
• To investigate the evolutionary origins and potential sub-neofunctionalization of HBx.

Main Methods:

• Comparative analysis of two distinct HBx structural topologies.
• Phylogenetic analysis of HBx sequences from human and non-human HBV strains.
• Molecular modeling using I-TASSER and AlphaFold, followed by molecular dynamics simulations.
• Structural alignment with existing experimental HBx structures.

Main Results:

• Phylogenetic analysis indicated potential zoonotic transmission between human and orangutan HBV.
• Identified conserved essential residues for transcription across mammalian HBV, alongside human-specific residues involved in localization and interaction.
• AlphaFold-predicted HBx structures were supported by molecular dynamics simulations and structural alignment, differing significantly from I-TASSER models.
• The AlphaFold-predicted HBx structure showed similarity to palmitoleoyl transferases.

Conclusions:

• AlphaFold provides a more reliable prediction of HBx structure compared to I-TASSER.
• HBx exhibits conserved functional sites across mammalian HBV and unique features in human strains, suggesting sub-neofunctionalization.
• The structural similarity to palmitoleoyl transferases offers a novel perspective on HBx's evolutionary origins and oncogenic mechanisms.