Structure-Based Mutations in the Herpes Simplex Virus 1 Glycoprotein B Ectodomain Arm Impart a Slow-Entry Phenotype

Fan, Qing; Kopp, Sarah J.; Connolly, Sarah A.; Longnecker, Richard

gB is trimeric and consists of five domains (Fig. 1A) . The postfusion gB structure adopts a hairpin conformation wherein the hydrophobic fusion loops that insert themselves into the host cell membrane reside at the same end of the molecule as the C terminus of the ectodomain, the site where the transmembrane domain would connect. This hairpin arrangement is common for the postfusion form of fusion proteins. A central coiled-coil core consisting of three ␣-helices in domain III contributes to the stability of the trimer. The C-terminal region of the ectodomain (domain V) consists of a long arm that extends down the length of the molecule and packs into a groove in the central coiled coil. The antiparallel packing of this arm against the coiled-coil helices is reminiscent of the six-helix bundle present in the postfusion conformation of class I fusion proteins. Formation of the class I six-helix bundle is proposed to help overcome the energy barrier to membrane fusion (18) . We hypothesize that gB refolds similarly to class I fusion proteins and that the arm packing against the coiled coil provides a driving force for the gB conformational change from its prefusion to its postfusion form. Interestingly, electron cryotomography of gB on vesicles revealed a gB conformation that lacks the coil-arm complex, supporting the concept that this complex may be absent from the prefusion form (19) .