Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • arn 509 First class II fusion proteins are known to transiti

    2022-03-31

    First, class II fusion proteins are known to transition from a (homo- or hetero-) pre-fusion dimer to a post-fusion trimer [57], [58], [59], [60], [61], [62] through a monomeric intermediate [63], [64], and a crystalline structure of a monomer of Rift Valley fever virus (a phlebovirus, member of the bunyaviridae family) Gc in an extended conformation, which may represent a transition intermediate, has been determined [65]. Indeed, several experiments have indicated that class II fusion arn 509 are monomeric when they interact with the target membrane [66]. Cryo-electron tomography (cryo-ET) analysis revealed bridge-like densities between acidified virions and liposomes with dimensions consistent with those of extended monomers for Rift Valley fever virus [67], Uukuniemi virus (another phlebovirus) [68] and Sindbis virus (an alphavirus) [69]. In the latter case, the orientation of the fusion glycoprotein (E1) relative to the virus surface appeared to be variable. The bridge-like densities between the virus and target membrane were either normal or at a slant relative to the virus surface. As suggested by the authors, this flexibility might allow E1 to bind the target membrane at different distances and curvatures [69]. The stage of the refolding process at which trimerization occurs still remains a matter of debate. Indeed, different conclusions have been drawn depending on the virus and the experiments. Biochemical data have suggested that, for Semliki Forest virus (an alphavirus) and Dengue virus (a flavivirus), trimer formation is relatively rapid and precedes the folding back of the carboxy-terminal domain [49], [50], [51]. On the other hand, for tick-borne encephalitis virus (a flavivirus), it has been suggested that trimerization may occur at a late stage of the refolding process [66]. Second, in the case of class I fusion glycoproteins, which are trimeric in both their pre- and post-fusion states [16], it is well known that their ectodomains are often monomeric when expressed in the absence of the transmembrane domain. To obtain a stable trimeric pre-fusion structure, the C-terminal part of the ectodomain is fused to a trimerization motif, based either on the transcription factor GCN4, as in the case of coronavirus S [70], parainfluenza virus 5 F glycoproteins [71] and Hendra virus F glycoprotein [72], or the T4 fibritin motif, as in the case of respiratory syncytial virus fusion glycoprotein [73]. Even for influenza HA, the dogma of the stability of the trimeric state all along the structural transition could be called into question in view of the growing number of crystalline structures that do not display any threefold symmetry (PDB entry codes: 4EDA, 5A3I 5K9K, 5K9O and 5IBL) [74], [75], [76], [77] (Fig. 4). More remarkably, in those crystal structures, the monomer structure is quite different from the structure of HA protomer in the trimeric pre-fusion state (Fig. 4b). Particularly, the helix A is longer as part of the loop has initiated its transition toward a helical conformation (Fig. 4b). On the other hand, the helix B is shorter (Fig. 4b). The fact that several crystalline structures of distinct HA subtypes contain a monomeric conformation suggests that it cannot be only a crystallization artifact and that those monomers might be transient intermediates that are trapped during the crystallization process. All those monomeric structures have been obtained in complex with a Fab, which may also have contributed to their catching in the crystal. If those structures correspond to real intermediates, they suggest a refolding pathway for HA monomer in which helix A elongation progressively displaces the loop in the structure of the helix B until this loop reaches the position it occupies in the post-fusion structure of HA2. It is worth noting that EM images and cryo-ET have also provided several views of the membrane remodeling events and some structural snapshots of HA during the fusion process [81], [82], [83], [84]. They are consistent with the initial formation of flexible extended intermediates which interact with the target membrane and refold into a post-fusion-like structure which is perpendicular to the axis of the fusion pore (i.e., parallel to the fusing membranes). However, the resolution of those structures is not sufficient to definitively conclude on their oligomeric state, although the authors suggest that they might be trimeric [84].