Epitope mapping of the PreS1 domain of the hepatitis B virus large surface protein

Kuroki, Kazuyuki; Floreani, Marco; Mimms, Larry; Ganem, Don

doi:10.1016/0042-6822(90)90032-m

Cited by 44 publications

(23 citation statements)

References 23 publications

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“…The accessibility of preS-specific epitopes of both proteins on the surface of secreted particles supports this notion (Heermann et al, 1984;Kuroki et al, 1990). The glycosylation of the preS2 region of M is further evidence for its luminal disposition.…”

Section: Introductionsupporting

confidence: 65%

“…These proteins are initially synthesized as transmembrane proteins of the ER membrane (Eble et al, 1986). Based on epitope mapping studies (Heermann et al, 1984;Kuroki et al, 1990), the current view of the transmembrane structure of the large L protein assumes that the entire preS region of L is on the luminal side of the ER membrane and is external in the virion (Heermann and Gerlich, 1991;Stirk et al, 1992). We demonstrate in the present study that the L protein adopts more than one transmembrane orientation.…”

Section: Discussionmentioning

confidence: 66%

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Novel transmembrane topology of the hepatitis B virus envelope proteins.

1995

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The small (S), middle (M) and large (L) envelope proteins of the hepatitis B virus (HBV) are initially synthesized as multispanning membrane proteins of the endoplasmic reticulum membrane. We now demonstrate that all envelope proteins synthesized in transfected cells or in a cell-free system adopt more than one transmembrane orientation. The L protein disposes its N-terminal preS domain both to the cytoplasmic and the luminal side of the membrane. This unusual topology does not depend on interaction with the viral nucleocapsid, but is preserved in secreted empty envelope particles. Pulse-chase analysis suggests a novel process of post-translational translocation leading to the non-uniform topology. Analysis of L deletion mutants indicates that the block to co-translational translocation can be attributed to a specific sequence within preS, suggesting that translocation of L may be regulated. Additional topological heterogeneity is displayed in the S region of the envelope proteins and in the S protein itself, as assayed in a cell-free system. S proteins integrated into microsomal membranes exhibit both a luminal and a cytoplasmic orientation of the internal hydrophilic region carrying the major antigenic determinants. This may explain the unusual partial glycosylation of the HBV envelope proteins.

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 66%

Novel transmembrane topology of the hepatitis B virus envelope proteins.

1995

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“…For instance, L protein might exhibit additional cytoplasmic sequences in its preS1 domain that could function in core recognition. However, epitope mapping studies suggest that most or all of the preS1 domain of L is initially the ER lumen, since (after budding) these sequences are displayed on the particle surface (25). Alternatively, if the only cytoplasmic sequences of the surface proteins are in the S domain, then it might be that the conformation of these sequences in L chains is different from that in S chains, or that interactions with L proteins change the conformation of cytoplasmic domains of S polypeptides during their aggregation.…”

Section: Discussionmentioning

confidence: 99%

The role of envelope proteins in hepatitis B virus assembly.

Bruss

Ganem

1991

Proc. Natl. Acad. Sci. U.S.A.

363

322

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Hepatitis B virus (HBV) particles are generated by budding of preformed cytoplasmic nucleocapsids into endoplasmic reticulum (ER) membranes containing the three viral envelope proteins (L, M, and S). We have examined the contributions of the envelope proteins to virion assembly by using cultured hepatoma cells transfected with mutant HBV genomes bearing lesions in the envelope coding regions. We show here that HBV nucleocapsids are not released from cells without expression ofenvelope proteins, implying an active role for these proteins in viral morphogenesis. S and L but not M proteins are necessary for virion production. L protein overexpression inhibits virion release, just as it inhibits the release of subviral hepatitis B surface antigen (HBsAg) particles. Mutant L proteins that are no longer capable of retaining HBsAg particles in the ER still allow virion formation, indicating that this ER retention reaction is not requlired for viral budding. Myristoylation of L protein is also dispensable for virion formation. A chimeric protein bearing foreign epitopes fused to the S protein can be incorporated into virions when coexpressed with the wild-type envelope proteins. Models for the dependence of virion formation on both L and S proteins are discussed.

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“…In all 18 candidate mutations were retained in the preS1/S2/S model out of a total of 152 parsimony informative sites (11.8%). Among these candidates, 10 have been previously described as epitopes (Kuroki et al, 1990;Meisel et al, 1994;Gripon et al, 2005) or as characteristic of chronic or fulminant hepatitis (Gunther et al, 1998;Koseki et al, 1999;Weinberger et al, 2000;Torresi, 2002). Only a single candidate mutation was found in the pc/core gene out of 53 parsimony informative sites.…”

Section: Candidate Mutationsmentioning

confidence: 99%

Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

et al. 2006

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Infection with the hepatitis B virus (HBV) leads to different disease outcomes, which can be broadly divided into three categories: acute mild infection, 'fulminant' and chronic hepatitis (long-term persistent form of the infection). The factors that influence the development of these different disease states are poorly understood and may include viral polymorphisms. To investigate this possibility, we analysed 116 published complete HBV genomes for which we knew disease outcome and had access to associated information on patients (age, sex and geographic origin). Our best statistical model correctly classified 72% of the cases and retained age and sex of the patient, as well as 29 candidate mutations. With the exception of one mutation in the X gene, all were located in the viral polymerase, suggesting this gene plays a critical role in clinical outcome. Our results highlight the importance of the genetics of HBV strains in the evolution of the disease and demonstrate that disease outcome can be predicted to a surprisingly large extent with a limited number of host and viral factors.

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Epitope mapping of the PreS1 domain of the hepatitis B virus large surface protein

Cited by 44 publications

References 23 publications

Novel transmembrane topology of the hepatitis B virus envelope proteins.

Novel transmembrane topology of the hepatitis B virus envelope proteins.

The role of envelope proteins in hepatitis B virus assembly.

Genome-wide characterisation of Hepatitis B mutations involved in clinical outcome

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