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  • Review Article
  • Published:

A structural perspective of the flavivirus life cycle

Nature Reviews Microbiology volume 3, pages 13–22 (2005)Cite this article

Key Points

  • Flavivirus genomes encode three structural proteins — capsid, membrane (M, expressed as prM, the precursor to M) and envelope (E) — that constitute the virus particle. Structures of several of the E and capsid proteins of flaviviruses have been solved to atomic resolution. In addition, cryo-electron microscopy has been used to visualize the whole structure of some flaviviruses at various stages of their life cycle. Combining these techniques to yield pseudo-atomic structures can further our understanding of dynamic processes in flaviviral life cycles.

  • The authors draw together a wealth of structural information to provide an overview of the interactions and conformational changes that occur when the flaviviruses (mainly dengue virus in this review) assemble and mature.

  • In the mature virion, the E and M proteins are partly buried in the virus membrane, one of a handful of proteins for which the structure within a membrane is known. Immature virion structures are also described and, together with the mature virion structure, enable the authors to review the conformational changes that accompany the virus maturation process.

  • Subviral particles, which assemble in the endoplasmic reticulum, provided the first insights into flavivirus assembly, and their production, composition and structure are described in this review.

  • Selected capsid protein structures are described, with particular reference to the early stages of virus assembly. Capsid proteins are important in the earliest step of assembly, through formation of a nucleocapsid core with genomic RNA

  • After entry into the host cell by receptor-mediated endocytosis, the acidic endosome environment triggers irreversible trimerization of the E protein, which exposes a fusion peptide and allows membrane fusion to release the virion into the cytoplasm. The authors review the structural features of E and how these relate to function, flavivirus receptor choice and the fusion process itself.

  • Finally, the authors discuss the class I and class II fusion mechanisms used by different enveloped viruses, in which very different structural proteins mediate membrane fusion.

Abstract

Dengue, Japanese encephalitis, West Nile and yellow fever belong to the Flavivirus genus, which is a member of the Flaviviridae family. They are human pathogens that cause large epidemics and tens of thousands of deaths annually in many parts of the world. The structural organization of these viruses and their associated structural proteins has provided insight into the molecular transitions that occur during the viral life cycle, such as assembly, budding, maturation and fusion. This review focuses mainly on structural studies of dengue virus.

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Figure 1: Flavivirus classification.
Figure 2: Membrane topology of the flavivirus structural proteins.
Figure 3: Structure of the ectodomain of the E protein in pre- and post-fusion conformations.
Figure 4: Packing of the E proteins in mature flavivirus virions.
Figure 5: Immature flavivirus particles.
Figure 6: Proposed rearrangement of the E proteins during maturation and fusion.
Figure 7: Proposed mechanisms for the membrane fusion process.

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Acknowledgements

We thank C. Jones, W. Zhang and Y. Zhang for many helpful and enthusiastic discussions and for providing figures. We gratefully acknowledge support to M.G.R. and R.J.K. from the National Institutes of Health.

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  1. Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, 47907-2054, Indiana, USA

    Suchetana Mukhopadhyay, Richard J. Kuhn & Michael G. Rossmann

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Correspondence to Michael G. Rossmann.

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DATABASES

Entrez

dengue virus

Japanese encephalitis virus

tick-borne encephalitis virus

West Nile virus

yellow fever virus

Protein Data Bank

dengue-2 capsid protein

dengue-2 E protein

JEV E protein

Kunjin capsid protein

TBEV E protein

FURTHER INFORMATION

Purdue University Structural Virology

Glossary

ECTODOMAIN

The part of the protein that is exterior to the lipid membrane.

TRIANGULATION NUMBER

The triangulation (T) number of an isometric virus designates the quasi-symmetry. In an icosahedron there are 60 asymmetric subunits. In an icosahedral particle, there are 60T protein subunits that comprise the structure.

METASTABLE

A system that is above its minimum-energy state, but which requires an energy input before it can reach a lower-energy state. As a result, a metastable system functions like a stable system provided the energy input is below a certain threshold.

DISORDERED

A molecule, or part of a molecule, that has no unique structure. Every molecule has a different structure in the disordered region

QUASI-SYMMETRY

The symmetry relationship between proteins in the asymmetric unit of an icosahedron, which is determined by the ability of each protein to have almost the same local environment.

ICOSAHEDRAL REFERENCE AXES

The specific symmetry axes in an icosahedron that are used to define the position of any point or atom in the icosahedron.

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Mukhopadhyay, S., Kuhn, R. & Rossmann, M. A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3, 13–22 (2005). https://doi.org/10.1038/nrmicro1067

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