Molecular gymnastics at the herpesvirus surface

Abstract

This review analyses recent structural results that provide clues about a possible molecular mechanism for the transmission of a fusogenic signal among the envelope glycoproteins of the herpes simplex virus on receptor binding by glycoprotein gD. This signal triggers the membrane-fusion machinery of the virus--contained in glycoproteins gB, gH and gL--to induce the merging of viral and cellular membranes, and to allow virus entry into target cells. This activating process parallels that of gamma-retroviruses, in which receptor binding by the amino-terminal domain of the envelope protein activates the fusogenic potential of the virion in a similar way, despite the different organization of the envelope complexes of these two types of viruses. Therefore, the new structural results on the interaction of gD with its receptors might also provide insights into the mechanism of fusogenic signal transmission in gamma-retroviruses. Furthermore, the fusion activation parallels with retroviruses, together with the recently reported structural homology of gB with the rhabdovirus envelope glycoprotein indicate that the complex entry apparatus of herpesviruses appears to be functionally related to that of simpler enveloped viruses.

Figure 1

Ribbon diagrams of different forms of the gD ectodomain and its complex with the herpesvirus entry-mediator molecule. The immunoglobulin-variable domain (IgV)/α3 ‘core' is depicted in white, the two proline-rich regions (PRRs) are shown in red and the amino-terminal arm that binds to the herpesvirus entry-mediator molecule (HVEM) is depicted in yellow. Disordered regions of the structure are shown as broken tubes. Some key gD amino acids are labelled. (A) Structure of the unliganded gD285t. (B) Structure of gD285t in complex with HVEM (shown in blue). The region roughly corresponding to the putative pro-fusion domain is labelled. (C) Structure of the full ectodomain gD306–Cys 307. The putative pro-fusion domain is constrained by the interaction between segments 290–306 and 23–45. The latter segment is engaged by the very N-terminal end (aa 1–21) on binding by HVEM (B) so that the carboxy-terminal segment becomes exposed. C-ter, carboxy terminus; N-ter, amino terminus; PFD, putative pro-fusion domain.

Figure 2

Schematic diagram illustrating the activation of the membrane-fusion machinery of herpes simplex virus 1 on gD interactions with receptors. The gD immunoglobulin-variable domain (IgV)/α3 core is represented by a white sphere, the amino-terminal arms are depicted in yellow and the proline-rich regions are depicted in red (as in Fig 1). The viral lipid bilayer is drawn with blue lipids facing the external side, and with grey lipids comprising the inner leaflet. The transmembrane helices of the viral proteins are drawn as cylinders (grey for gD) and the cytoplasmic tail is represented by a diamond shape. (A) gD is drawn in its putative dimeric conformation at the virus surface (extrapolated from the structure of the Cys 307 dimer, with the disulphide linking the two protomers in the region immediately preceding the transmembrane helices; see the main text), with the twofold axis vertical in the plane of the membrane. In this conformation, the N-terminal end is able to interact with the receptor, and the pro-fusion domain is involved in dimer interactions, as well as with the region spanning amino acids 24–45 (Fig 1). (B) The interaction with the receptor (herpes virus entry-mediator molecule (HVEM) in this case) is proposed to disrupt the dimer interface and induce the flipping of the gD core away from the viral membrane, resulting in exposure of the putative pro-fusion domain to activate the HSV-1-fusion machinery. gB and the gH/gL heterodimer are depicted inside broken lines with a question mark, to indicate that the stoichiometry and the gD interaction site are not known. C-ter, carboxy terminus; N-ter, amino terminus; PFD, putative pro-fusion domain.

Figure 3

Schematic diagram of the organization of envelope proteins gD, gH and gD/gH of the porcine pseudorabies virus compared with that of the envelope protein of the murine leukaemia virus Friend. The immunoglobulin-variable domain (IgV)/α3 core is depicted in yellow, the proline-rich regions (PRRs) are depicted in red, and the signal sequence (SS) and transmembrane (TM) segments are cross-hatched. The fusion peptide at the amino-terminal end of the transmembrane subunit of Fr-MLV is diagonally striped. aa, amino acids; C, carboxy terminus; ENV, single envelope glycoprotein precursor; Fr-MLV, Friend murine leukaemia virus; PRV, porcine pseudorabies virus; N, amino terminus.

Félix A.Rey