Fusion on a Pedestal: The Structure of the Full-Length HSV-1 Fusogen gB

All enveloped viruses must catalyze the fusion of their surrounding membrane with that of their target cell. In herpesviruses, fusion is powered by a large structural rearrangement of the trimeric fusogen gB, with help from viral glycoproteins gD and gH/gL. Although the structure of the postfusion gB ectodomain has been solved, the architecture of the membrane-interacting portion of gB - its membrane proximal region (MPR), transmembrane domain (TMD), and cytoplasmic domain (CTD) - is unknown. These domains both facilitate and regulate fusion, but the lack of structural information on them has hindered reconstruction of the gB refolding process. To fill this gap, we have crystallized full-length, postfusion gB in a detergent-amphipol environment. The resulting structure is the first to encompass the membrane-spanning portion of a viral fusogen in its postfusion conformation. In each protomer of the gB trimer, the MPR is a lipid embedded helix that forms a platform beneath the ectodomain. The TMD helices traverse the membrane at an angle, creating a flexible conduit that could transmit the status of the regulatory CTD below. In the CTD, the three protomers form a shallow basket bounded by a long helix that angles upward toward the membrane. While the remainder of the CTD is unstructured in these crystals, electron spin resonance (ESR) spectroscopy data indicate that many of these distal residues form an amphipathic helix embedded in the outer bilayer. Protein/protein and protein/membrane contacts may enable the CTD to restrain fusion by acting as a clamp that braces against the bilayer. These results thus present a possible mechanism for regulation of gB mediated fusion and a strategy for capturing another critical gB form - the elusive prefusion conformation.