Vesicular stomatitis virus (VSV) is an oncolytic rhabdovirus and its glycoprotein G is widely used to pseudotype other viruses for gene therapy. Low-density lipoprotein receptor (LDL-R) serves as a major entry receptor for VSV. Here we report two crystal structures of VSV G in complex with two distinct cysteine-rich domains (CR2 and CR3) of LDL-R, showing that their binding sites on G are identical. We identify two basic residues on G, which are essential for its interaction with CR2 and CR3. Mutating these residues abolishes VSV infectivity even though VSV can use alternative receptors, indicating that all VSV receptors are members of the LDL-R family. Collectively, our data suggest that VSV G has specifically evolved to interact with receptor CR domains. These structural insights into the interaction between VSV G and host cell receptors provide a basis for the design of recombinant viruses with an altered tropism.

/pdf/structural-basis-for-the-recognition-of-ldl-receptor-family-1f562blnhb.pdf

Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein.

Structural Analysis of Rabies Virus Glycoprotein Reveals pH-Dependent Conformational Changes and Interactions with a Neutralizing Antibody

Cell entry of enveloped viruses requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation. By identification of conserved sequence signatures and molecular dynamics simulations, we devised a mutation that stabilized this form. Functionally locking gB allowed the structural determination of its membrane-embedded prefusion conformation at sub-nanometer resolution and enabled the unambiguous fit of all ectodomains. The resulting pseudo-atomic model reveals a notable conservation of conformational domain rearrangements during fusion between HSV-1 gB and the vesicular stomatitis virus glycoprotein G, despite their very distant phylogeny. In combination with our comparative sequence-structure analysis, these findings suggest common fusogenic domain rearrangements in all class III viral fusion proteins.

The prefusion structure of herpes simplex virus glycoprotein B

Rift Valley fever virus (RVFV), like many other Bunyaviridae family members, is an emerging human and animal pathogen. Bunyaviruses have an outer lipid envelope bearing two glycoproteins, GN and GC, required for cell entry. Bunyaviruses deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane. The molecular mechanism of this key entry step is unknown. The crystal structure of RVFV GC reveals a class II fusion protein architecture found previously in flaviviruses and alphaviruses. The structure identifies GC as the effector of membrane fusion and provides a direct view of the membrane anchor that initiates fusion. A structure of nonglycosylated GC reveals an extended conformation that may represent a fusion intermediate. Unanticipated similarities between GC and flavivirus envelope proteins reveal an evolutionary link between the two virus families and provide insights into the organization of GC in the outer shell of RVFV.

Crystal structure of glycoprotein C from Rift Valley fever virus

http://www.cell.com/article/S1931312822003602/pdf

Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies

Proteomic studies have established that Trz1, Nuc1 and mutarotase form a complex in yeast. Trz1 is a β-lactamase-type RNase composed of two β-lactamase-type domains connected by a long linker that is responsible for the endonucleolytic cleavage at the 3'-end of tRNAs during the maturation process (RNase Z activity); Nuc1 is a dimeric mitochondrial nuclease involved in apoptosis, while mutarotase (encoded by YMR099C) catalyzes the conversion between the α- and β-configuration of glucose-6-phosphate. Using gel filtration, small angle X-ray scattering and electron microscopy, we demonstrated that Trz1, Nuc1 and mutarotase form a very stable heterohexamer, composed of two copies of each of the three subunits. A Nuc1 homodimer is at the center of the complex, creating a two-fold symmetry and interacting with both Trz1 and mutarotase. Enzymatic characterization of the ternary complex revealed that the activities of Trz1 and mutarotase are not affected by complex formation, but that the Nuc1 activity is completely inhibited by mutarotase and partially by Trz1. This suggests that mutarotase and Trz1 might be regulators of the Nuc1 apoptotic nuclease activity.

Trz1, the long form RNase Z from yeast, forms a stable heterohexamer with endonuclease Nuc1 and mutarotase.

Photosome membranes merge and organize tending towards rhombohedral symmetry when light is emitted.

Study of membrane deformations induced by Hepatitis C protein NS4B and its terminal amphipathic peptides

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 toward a trimeric post-fusion state via monomeric intermediates. Here, we present the structure of the G fusion protein at intermediate pH for two vesiculoviruses, vesicular stomatitis virus (VSV) and Chandipura virus (CHAV), which is responsible for deadly encephalopathies. First, a CHAV G crystal structure shows two intermediate conformations forming a flat dimer of heterodimers. On virions, electron microscopy (EM) and tomography reveal monomeric spikes similar to one of the crystal conformations. In solution, mass spectrometry shows dimers of G. Finally, mutations at a dimer interface, involving fusion domains associated in an antiparallel manner to form an intermolecular β-sheet, affect G fusion properties. The location of the compensatory mutations restoring fusion activity strongly suggests that this interface is functionally relevant. This work reveals the range of G structural changes and suggests that G monomers can re-associate, through antiparallel interactions between fusion domains, into dimers that play a role at some early stage of the fusion process.

/pdf/structural-intermediates-in-the-fusion-associated-transition-53541x7clu.pdf

Structural intermediates in the fusion-associated transition of vesiculovirus glycoprotein.

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Trz1, the long form RNase Z from yeast, forms a stable heterohexamer with endonuclease Nuc1 and mutarotase.

Photosome membranes merge and organize tending towards rhombohedral symmetry when light is emitted.

Study of membrane deformations induced by Hepatitis C protein NS4B and its terminal amphipathic peptides

Structural intermediates in the fusion-associated transition of vesiculovirus glycoprotein.