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  • Impact of structural dynami...
    Stiasny, Karin; Medits, Iris; Roßbacher, Lena; Heinz, Franz X.

    The FEBS journal, April 2023, Volume: 290, Issue: 8
    Journal Article

    Flaviviruses comprise a number of mosquito‐ or tick‐transmitted human pathogens of global public health importance. Advances in structural biology techniques have contributed substantially to our current understanding of the life cycle of these small enveloped RNA viruses and led to deep insights into details of virus assembly, maturation and cell entry. In addition to large‐scale conformational changes and oligomeric rearrangements of envelope proteins during these processes, there is increasing evidence that smaller‐scale protein dynamics (referred to as virus “breathing”) can confer extra flexibility to these viruses for the fine‐tuning of their interactions with the immune system and possibly with cellular factors they encounter in their complex ecological cycles in arthropod and vertebrate hosts. In this review, we discuss how work with tick‐borne encephalitis virus has extended our view on flavivirus breathing, leading to the identification of a novel mechanism of antibody‐mediated infection enhancement and demonstrating breathing intermediates of the envelope protein in the process of membrane fusion. These data are discussed in the context of other flaviviruses and the perspective of a potential role of virus breathing to cope with the requirements of adaptation and replication in evolutionarily very different hosts. Small‐scale dynamics of the major envelope protein E of flaviviruses (“virus breathing”) together with binding of specific antibodies can promote fusion‐loop exposure and insertion into plasma membranes of target cells, providing the basis for a special mechanism of antibody‐mediated enhanced infection. Upon cellular uptake by endocytosis, dynamic “breathing” intermediates are functionally important for the structural conversions of E into a post‐fusion conformation to drive membrane fusion in the endosome.