Model of class I fusion protein–mediated membrane fusion. (A and B) The trimeric paramyxovirus F protein contains 2 hydrophobic domains: the fusion peptide and the transmembrane-spanning domain. Each is adjacent to 1 of 2 HR regions, HR-N and HR-C. (B) The F protein binds to a receptor on the host cell membrane, causing a conformational change and subsequent insertion of the hydrophobic fusion peptide into the host cell membrane. (C) Multiple F protein trimers are believed to mediate the fusion process. Protein refolding occurs when the host and viral cell membranes bend toward each other (D), and formation of a hemifusion stalk allows the lipids on the outer part of the membranes to interact (E). (F) When protein refolding is completed, the fusion peptide and the transmembrane domain are antiparallel in the same membrane, which creates the most stable form of the fusion protein. Figure modified with permission from Nature (40).