Structure of Hepatitis B Surface Antigen from Subviral Tubes Determined by Electron Cryomicroscopy

Short, Judith M.; Chen, Shao-Xia; Roseman, Alan M.; Butler, P.J.G.; Crowther, R. Anthony

doi:10.1016/j.jmb.2009.04.059

Cited by 37 publications

(47 citation statements)

References 23 publications

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“…Reprinted with permission provides a structural model for the HBsAg vaccine particle that is consistent with previous results regarding the antigenic features, lipid-protein arrangement, and overall particle architecture (Mangold et al 1995;Stirk et al 1992;Le Duff et al 2009;Salisse and Sureau 2009;Gilbert et al 2005;Greiner et al 2010;Short et al 2009). …”

Section: Cryotem Studiessupporting

confidence: 84%

Recombinant Virus-like Particle Protein Vaccines

Sitrin¹,

Zhao

Potter

et al. 2014

Vaccine Analysis: Strategies, Principles, and Control

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Section: Cryotem Studiessupporting

confidence: 84%

Recombinant Virus-like Particle Protein Vaccines

Sitrin¹,

Zhao

Potter

et al. 2014

Vaccine Analysis: Strategies, Principles, and Control

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“…In a model for the arrangement of HBV envelope proteins in filamentous SVP deduced from electron cryomicroscopy, the proteins form tetramers and their TMs are densely packed in a middle ring of approximately 3 nm in thickness around the helical axis of the filament (21). This size corresponds to the thickness of a lipid bilayer, and the fraction of 21% of low-density areas in the model fits well to the low content of 25% (wt/wt) of lipids in SVP (22).…”

Section: Discussionmentioning

confidence: 99%

Role of Transmembrane Domains of Hepatitis B Virus Small Surface Proteins in Subviral-Particle Biogenesis

Siegler

Bruss

2013

J Virol

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The hepatitis B virus (HBV) surface proteins not only are incorporated into the virion envelope but in addition form subviral particles (SVP) consisting solely of surface proteins and lipids. Heterologous expression of the small HBV envelope protein S produces secreted spherical SVP 20 nm in diameter, with approximately 100 S molecules per particle. The pathway leading from the initial S translation product as a multispanning transmembrane protein to the final SVP is largely unknown. To investigate the role of the four transmembrane domains (TM) of S in this process, we introduced mutations in these regions and characterized their effects on SVP formation in transfected Huh7 cells. We found that the insertion of one amino acid in the center of the ␣-helix of TM1 or the exchange of TM1 with a heterologous TM blocked SVP release and SVP formation by coexpressed wildtype S chains in a transdominant negative fashion. Surprisingly, this effect was partially neutralized when the mutations were expressed in the background of the HBV surface protein M, suggesting that mutations in TM1 could partially be complemented by the pre-S2 domain. The exchange of TM2 with heterologous TMs that form ␣-helices of the same lengths was also incompatible with SVP formation. However, these mutants no longer blocked SVP formation by coexpressed wild-type S. We conclude that TM2 is essential for the stable assembly of S chains by establishing intramembrane interactions. Hepatitis B virus (HBV) causes chronic infections of the liver in more than 350 million people worldwide and an increased risk for the development of hepatocellular carcinoma in these individuals (1). Today's options for the treatment of persistent HBV infections are unsatisfying. Therefore, the prevention of HBV infections is particularly important and can be achieved by active vaccination. The most common vaccine consists of the major HBV envelope protein S expressed in yeast. This protein is peculiar as it not only is incorporated into the envelope of virions which have a diameter of 42 nm but, together with host lipids, also assembles into spherical or filamentous lipoprotein particles of 20 nm in diameter (2). Such subviral particles (SVP) are secreted in great excess over virions from infected hepatocytes. Spherical SVP containing approximately 100 protein molecules are also formed by cells expressing the S protein in the absence of any other HBVencoded protein and represent the antigenic component of HBV vaccines.The gene encoding the S protein constitutes the 3= end of a longer continuous open reading frame that is divided into the regions pre-S1, pre-S2, and S. Two further HBV envelope proteins, M and L, are encoded by the pre-S2 plus S and by the pre-S1 plus pre-S2 plus S sequences, respectively. Therefore, all three proteins share the S domain at their C termini. Virion envelopes contain the three proteins S, M, and L at a ratio of approximately 4:1:1. Natural spherical SVP contain mainly S proteins and some M proteins but only small amounts of L, while filamen...

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“…Although these envelopes only loosely interact with cores (Seitz et al, 2007; Stannard and Hodgkiss, 1979), the organization of surface proteins, despite averaging techniques that result in loss of much of the detail, has also been observed in helical reconstructions of subviral HBsAg particles (Short et al, 2009). …”

Section: A Standard Overview Of the Hbv Lifecycle And Hbvmentioning

confidence: 99%

Core protein: A pleiotropic keystone in the HBV lifecycle

et al. 2015

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Hepatitis B Virus (HBV) is a small virus whose genome has only four open reading frames. We argue that the simplicity of the virion correlates with a complexity of functions for viral proteins. We focus on the HBV core protein (Cp), a small (183 residue) protein that self-assembles to form the viral capsid. However, its functions are a little more complicated than that. In an infected cell Cp modulates every step of the viral lifecycle. Cp is bound to nuclear viral DNA and affects its epigenetics. Cp correlates with RNA specificity. Cp assembles specifically on a reverse transcriptase-viral RNA complex or, apparently, nothing at all. Indeed Cp has been one of the model systems for investigation of virus self-assembly. Cp participates in regulation of reverse transcription. Cp signals completion of reverse transcription to support virus secretion. Cp carries both nuclear localization signals and HBV surface antigen (HBsAg) binding sites; both of these functions appear to be regulated by contents of the capsid. Cp can be targeted by antivirals -- while self-assembly is the most accessible of Cp activities, we argue that it makes sense to engage the broader spectrum of Cp function. This article forms part of a symposium in Antiviral Research on “From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B: an unfinished story.”

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Structure of Hepatitis B Surface Antigen from Subviral Tubes Determined by Electron Cryomicroscopy

Cited by 37 publications

References 23 publications

Recombinant Virus-like Particle Protein Vaccines

Recombinant Virus-like Particle Protein Vaccines

Role of Transmembrane Domains of Hepatitis B Virus Small Surface Proteins in Subviral-Particle Biogenesis

Core protein: A pleiotropic keystone in the HBV lifecycle

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