Monomeric Intermediates Formed by Vesiculovirus Glycoprotein during Its Low-pH-induced Structural Transition

Abstract

Vesiculoviruses enter cells by membrane fusion, driven by a large, low-pH-induced, conformational change in the fusion glycoprotein (G) that involves transition from a trimeric pre-fusion to a trimeric post-fusion state. G is the model of class III fusion glycoproteins which also includes the fusion glycoproteins of herpesviruses (gB) and baculoviruses (gp64). Class III fusion proteins combine features of the previously characterized class I and class II fusion proteins. In this review, we first present and discuss the data that indicate that the Vesiculovirus G structural transition proceeds through monomeric intermediates. Then, we focus on a recently determined crystal structure of the Chandipura virus G ectodomain that contained two monomeric intermediate conformations of the glycoprotein, revealing the chronological order of the structural changes in the protein and offering a detailed pathway for the conformational change, in agreement with electron microscopy data. In the crystal, the intermediates were associated through their fusion domain in an antiparallel manner to form an intermolecular β-sheet. Mutagenesis indicated that this interface is functionally relevant. All those structural data challenge the current model proposed for viral membrane fusion. Therefore, we wonder if this mode of operating is specific to Vesiculovirus G and discuss data indicating that class II fusion glycoproteins are monomeric when they interact with the target membrane but also crystal structures suggesting the existence of non-trimeric intermediates for influenza hemagglutinin which is the prototype of class I fusion proteins.

Crystal structure of Mokola virus glycoprotein in its post-fusion conformation

“…Although MOKV G has been crystallized in a monomeric conformation, EM reveals that, at low pH, it adopts a trimeric post-fusion conformation at the viral surface, which indicates once again that for both lyssaviruses and vesiculoviruses the trimer is less stable than class I fusion glycoproteins, as largely documented in the literature [11,39]. This is in agreement with the model that, for rhabdoviruses, the structural transition proceeds through monomeric intermediates [27,40].…”

Transient opening of trimeric prefusion RSV F proteins

“…Previous studies have implicated the F 2 subunit in species specificity of RSV and in fusogenicity of F 31,32 . However, the conformational changes observed in the CR9501-bound monomer are subtle, in contrast to what has been observed in monomeric structures of antibody-bound influenza hemagglutinin (HA) in which conformational changes indicative of triggering are present 41–44 . This is likely because CR9501 also contacts the α2–α3 helices, which would prevent conformational changes associated with fusion.…”

The Stabilities of the Soluble Ectodomain and Fusion Peptide Hairpins of the Influenza Virus Hemagglutinin Subunit II Protein Are Positively Correlated with Membrane Fusion

“…A monomer fraction for HA2 in SEC correlates with monomer fractions of the initial HA1/HA2 complex under some conditions, as well as large monomer fractions for gp41 under some conditions. 47, 48, 50, 52, 56, 57, 70 For both HA2 and gp41, there is a significant structural rearrangement between the initial trimeric HA1/HA2 or gp160 complex, and the final trimer-of-hairpins without the receptor proteins. Transient dissociation of HA2 and gp41 into monomers may be functionally important because monomer rearrangement into a hairpin followed by association into a trimer-of- hairpins may be topologically more straightforward than a concerted rearrangement of trimeric protein.…”