Limits...
Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

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Structural constraints and HBV diversity. The crystal structure formed by four HBVc subunits was displayed and coloured using RasMol software. The position of the amino acid identified as essential for virion formation (violet) or for both capsid and virion assembly (green) [23] are shown. The rest of the colour coding is as shown in fig 6.
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Figure 7: Structural constraints and HBV diversity. The crystal structure formed by four HBVc subunits was displayed and coloured using RasMol software. The position of the amino acid identified as essential for virion formation (violet) or for both capsid and virion assembly (green) [23] are shown. The rest of the colour coding is as shown in fig 6.

Mentions: A detailed alanine mutagenesis study has been carried out mapping those amino acids critical to proper capsid formation, and/or required for envelopment and virion formation [23]. Mutation of 24 amino acids was found to block capsid formation, virion formation or both. The position of these mutations on the 3D structure is shown in fig 7. The position of this set of mutations is quite widely distributed over the structure, suggesting multiple essential interactions are absolutely required either for proper capsid assembly, or for envelope and virion assembly. However, interestingly, all but one of these 24 amino acids were found to be invariant in the data set analysed in this study. The only exception observed was at position 129, where changing proline to alanine was found to block both capsid and virion formation. Both glutamine and threonine are found in a proportion of virus sequences at this position, and further mutagenesis will be required to clarify the constraints imposed by the requirements of virion formation on the sequence at this particular position. Thus the structural requirements of virion assembly seem to impose a significant restraint on HBVc diversity. However, several positions which were found to tolerate alanine mutagenesis in terms of capsid/virion assembly were nevertheless invariant in the set of sequences examined here. The overall high degree of conservation in HBVc therefore probably reflects the multiple functions required from this protein, including control of intracellular targeting [5], pregenome/DNA polymerase packaging, capsid disassembly and viral maturation.


Variability and conservation in hepatitis B virus core protein.

Chain BM, Myers R - BMC Microbiol. (2005)

Structural constraints and HBV diversity. The crystal structure formed by four HBVc subunits was displayed and coloured using RasMol software. The position of the amino acid identified as essential for virion formation (violet) or for both capsid and virion assembly (green) [23] are shown. The rest of the colour coding is as shown in fig 6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1173110&req=5

Figure 7: Structural constraints and HBV diversity. The crystal structure formed by four HBVc subunits was displayed and coloured using RasMol software. The position of the amino acid identified as essential for virion formation (violet) or for both capsid and virion assembly (green) [23] are shown. The rest of the colour coding is as shown in fig 6.
Mentions: A detailed alanine mutagenesis study has been carried out mapping those amino acids critical to proper capsid formation, and/or required for envelopment and virion formation [23]. Mutation of 24 amino acids was found to block capsid formation, virion formation or both. The position of these mutations on the 3D structure is shown in fig 7. The position of this set of mutations is quite widely distributed over the structure, suggesting multiple essential interactions are absolutely required either for proper capsid assembly, or for envelope and virion assembly. However, interestingly, all but one of these 24 amino acids were found to be invariant in the data set analysed in this study. The only exception observed was at position 129, where changing proline to alanine was found to block both capsid and virion formation. Both glutamine and threonine are found in a proportion of virus sequences at this position, and further mutagenesis will be required to clarify the constraints imposed by the requirements of virion formation on the sequence at this particular position. Thus the structural requirements of virion assembly seem to impose a significant restraint on HBVc diversity. However, several positions which were found to tolerate alanine mutagenesis in terms of capsid/virion assembly were nevertheless invariant in the set of sequences examined here. The overall high degree of conservation in HBVc therefore probably reflects the multiple functions required from this protein, including control of intracellular targeting [5], pregenome/DNA polymerase packaging, capsid disassembly and viral maturation.

Bottom Line: Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid.The structural requirements of capsid assembly are likely to play a major role in limiting diversity.The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology and Molecular Pathology, University College London, W1T 4JF UK. b.chain@ucl.ac.uk

ABSTRACT

Background: Hepatitis B core protein (HBVc) has been extensively studied from both a structural and immunological point of view, but the evolutionary forces driving sequence variation within core are incompletely understood.

Results: In this study, the observed variation in HBVc protein sequence has been examined in a collection of a large number of HBVc protein sequences from public sequence repositories. An alignment of several hundred sequences was carried out, and used to analyse the distribution of polymorphisms along the HBVc. Polymorphisms were found at 44 out of 185 amino acid positions analysed and were clustered predominantly in those parts of HBVc forming the outer surface and spike on intact capsid. The relationship between HBVc diversity and HBV genotype was examined. The position of variable amino acids along the sequence was examined in terms of the structural constraints of capsid and envelope assembly, and also in terms of immunological recognition by T and B cells.

Conclusion: Over three quarters of amino acids within the HBVc sequence are non-polymorphic, and variation is focused to a few amino acids. Phylogenetic analysis suggests that core protein specific forces constrain its diversity within the context of overall HBV genome evolution. As a consequence, core protein is not a reliable predictor of virus genotype. The structural requirements of capsid assembly are likely to play a major role in limiting diversity. The phylogenetic analysis further suggests that immunological selection does not play a major role in driving HBVc diversity.

Show MeSH
Related in: MedlinePlus