FIG. 1.

The common trimer-of-hairpins pathway of membrane fusion. (A) The model depicts a Class I fusion protein, but related structures (e.g., prehairpins and trimers-of-hairpins) form for Class II and III proteins, which also promote membrane merger through stages of close apposition (iv), hemifusion (v), small fusion pores (not shown), and large fusion pores (vi). See Table 2 and text for comparisons among the different classes of viral fusion proteins. The depicted Class I fusion protein is one that does not require any other viral surface proteins for fusion (e.g., influenza HA or a retroviral Env); it contains both a receptor binding subunit (labeled rb in image i) and a fusion subunit (labeled f in images i to iii). The target and viral membranes are, respectively, at the top and bottom of the images. The receptor binding subunit (rb) is not shown beyond image i as its location at the later stages is not known; in all cases studied, however, the rb subunit of this type of class I fusion protein must move out of the way, thus unclamping the fusion subunit in the metastable fusion competent state and allowing fusion to proceed. For Class I fusion proteins six helix bundles (6HBs) are seen in their bundle (v) and trimer-of-hairpins (vi) forms; the length and position of the 6HB varies for different proteins. The starting (i) and final (vi) images represent structures that are known for several viral fusion proteins; high level structural information is currently lacking on the intermediates. (B) The key features of a class I fusion protein from N- to C-terminus: a fusion peptide (FP) at or near the N-terminus, an N-heptad repeat (N-HR aka HR1 or HRA), a C-heptad repeat (C-HR aka HR2 or HRB), a transmembrane domain (TMD), and a cytoplasmic tail (squiggle). Linkers of variable lengths are indicated as straight lines. (The // between the N- and C-heptad repeats indicates that the length of these linkers varies considerably). Peptide analogs of the N-HR and C-HR helices can inhibit fusion and infection.