A structural perspective of the flavivirus life cycle

• Published in: Nature reviews. Microbiology 2005-01, Vol.3 (1), p.13-22
• Main Authors: Rossmann, Michael G, Mukhopadhyay, Suchetana, Kuhn, Richard J
• Format: Article
• Language: English
• Subjects: Amino acids; Biomedical and Life Sciences; Capsid Proteins - chemistry; Capsid Proteins - metabolism; Cytoplasm; Dengue fever; Dengue virus; Encephalitis; Endoplasmic reticulum; Epidemics; Flavivirus; Flavivirus - chemistry; Flavivirus - physiology; Genomes; Glycoproteins; Infectious Diseases; Japanese encephalitis virus; Life cycles; Life Sciences; Medical Microbiology; Membrane Fusion; Microbiology; Models, Molecular; Parasitology; Pathogens; Peptides; Protein Structure, Tertiary; Proteins; review-article; Serology; Structure-Activity Relationship; Vector-borne diseases; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism; Viral Structural Proteins - chemistry; Viral Structural Proteins - metabolism; Virion - metabolism; Virology; Virus Replication; Viruses; West Nile virus
• ISSN: 1740-1526; 1740-1534
• DOI: 10.1038/nrmicro1067

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. 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