Class I Fusion Proteins

The first step in a fusion process triggered by a class I fusion protein is an activation event that releases a viral fusion peptide, which interacts with the target membrane. In the second step, a conformational change of the entire fusion protein brings the viral and target membranes into close proximity. Functional separation of these two steps ensures that the fusion mechanism is activated only when the target membrane is within reach. As implied in a very similar way for SNARE-mediated membrane fusion (see Sect. 2.2), the free energy difference between the pre- and post-fusion states of the fusion protein is the driving force for membrane deformation and ultimately fusion (Weissenhorn et al. 2007).

Recognition of target structures and membrane fusion are mediated by viral glycoproteins exposed at the surface of enveloped viruses. These glycoproteins contain a receptor-binding region and a part responsible for membrane fusion. Both are synthesized as a single polypeptide chain that assembles into a homotrimer before being proteolytically cleaved into two subunits, a receptor-binding protein and a fusion protein. The subunits remain closely associated and represent the metastable, fusion-competent state. The receptor-binding protein is entirely external to the viral membrane and contains specificity determinants for target-membrane receptor recognition. By contrast, the fusion protein is an integral membrane protein made up of a C-terminal endodomain, a transmembrane region, and an N-terminal ectodomain. The ectodomain contains two heptad repeat regions (HR1 and HR2), which are separated by a hinge domain, and an N-terminal hydrophobic sequence known as the fusion peptide, which makes contact with the target membrane. HR1 is present as a central trimeric coiled-coil stalk already in the pre-fusion complex. Activation of the fusion complex upon receptor binding leads to a number of sequential conformational changes (Fig. 3). First, the fusion protein is released from its complex with the receptor-binding protein, thereby exposing and extending the fusion peptide to establish interaction with the target membrane. Then, HR2 folds back onto the hydrophobic outer groove of the central trimeric coiled-coil stalk of HR1, thus forming a stable six-helix bundle. This refolding brings the viral

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