Abstract
Hepatitis B virus (HBV) is an important but difficult to study human pathogen. Most basics of the hepadnaviral life-cycle were unraveled using duck HBV (DHBV) as a model although DHBV has a capsid protein (CP) comprising ~260 rather than ~180 amino acids. Here we present high-resolution structures of several DHBV capsid-like particles (CLPs) determined by electron cryo-microscopy. As for HBV, DHBV CLPs consist of a dimeric α-helical frame-work with protruding spikes at the dimer interface. A fundamental new feature is a ~ 45 amino acid proline-rich extension in each monomer replacing the tip of the spikes in HBV CP. In vitro, folding of the extension takes months, implying a catalyzed process in vivo. DHBc variants lacking a folding-proficient extension produced regular CLPs in bacteria but failed to form stable nucleocapsids in hepatoma cells. We propose that the extension domain acts as a conformational switch with differential response options during viral infection.
Highlights
Hepadnaviruses are a family of small enveloped retrotranscribing DNA viruses
The characteristic broad spikes of the DHBV CP (DHBc) capsid-like particles (CLPs) were only visible at lower density thresholds but disappeared at higher density thresholds, suggesting a markedly higher structural variability in the extensions than in the core of the spikes
To reveal a potential virological relevance of the extension domain we examined the impact of extension domain-affecting mutations on capsid expression, viral nucleic acid packaging and reverse transcription in transfected LMH cells, an avian hepatoma line supporting formation of infectious duck HBV (DHBV) (Condreay et al, 1990; Dallmeier et al, 2008)
Summary
Hepadnaviruses (hepatotropic DNA viruses) are a family of small enveloped retrotranscribing DNA viruses. Despite basal similarities in genome size, genetic organization and replication strategy the avian viruses exhibit characteristic differences to human and the other mammalian HBVs (genus orthohepadnaviridae). They lack an X protein, a regulator of cccDNA transcription (Livingston et al, 2017), and a medium sized (M) envelope or surface protein besides the small (S) and large (L) forms; in addition, the avian virus surface proteins are smaller, with only three predicted transmembrane helices versus four in the orthohepadnaviruses. A key step would be knowledge of their structure but, ironically, here DHBV lags much behind HBV for which various structures are available for recombinant capsid-like particles (CLPs)
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