Allosteric conformational changes of human HBV core protein transform its assembly

Chuang Liu,Chang-Cheng Yin,Hong-Song Chen,Guizhen Fan,Zhao Wang

doi:10.1038/s41598-017-01568-9

Chuang Liu, Chang-Cheng Yin + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-01568-9

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Abstract

Hepatitis B Virus core protein (HBc) has multiple roles in the viral lifecycle: viral assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions. HBc displays assembly polymorphism - it can assemble into icosahedral capsid and aberrant non-capsid structures. It has been hypothesized that the assembly polymorphism is due to allosteric conformational changes of HBc dimer, the smallest assembly unit, however, the mechanism governing the polymorphic assembly of the HBc dimer is still elusive. By using the experimental antiviral drug BAY 41-4109, we successfully transformed the HBc assembly from icosahedral capsid to helical tube. Structural analyses of HBc dimers from helical tubes, T = 4 icosahedral capsid, and sheet-like HBc ensemble revealed differences within the inter-dimer interface. Disruption of the HBc inter-dimer interface may likely promote the various assembly forms of HBc. Our work provides new structural insights into the HBV assembly mechanism and strategic guide for anti-HBV drug design.

Highlights

Biological processes, such as gene replication, transcription and translation, are performed by macromolecular complexes
HAPs induce assembly-active states (HBcAct) at stoichiometric levels but stabilize non-capsid polymers at higher concentrations[10, 26,27,28]. Consistent with these findings, we observed that BAY 41-4109 affects Hepatitis B Virus core protein (HBc) assembly in a dose-dependent manner: (1) in the absence of BAY 41-4109, HBc dimers assemble normally into icosahedral particles with diameters of 31 nm and 28 nm, indicating that free HBc dimers could assemble into both T = 4 and T = 3 icosahedral capsids (Figure S2a)
It has been hypothesized that the assembly polymorphism is due to allosteric conformational changes of HBc dimer, the smallest assembly unit[20]

Summary

Introduction

Biological processes, such as gene replication, transcription and translation, are performed by macromolecular complexes. The correct assembly of macromolecules into a structurally and functionally relevant form is a key step for a biological process to be carried out successfully. The conformational differences of HBc dimers of the tubular ensemble from the icosahedral capsid and the sheet-like ensemble are subtle, with only lateral and rotational helix movement. These subtle conformational changes alter the inter-dimer interactions, leading to a smaller contact area between HBc dimers. This renders the icosahedral capsid thermodynamically unfavourable due to the weakened inter-dimer interactions and drives the HBc assembly into larger ensemble, the helical tube

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