Unity in diversity: shared mechanism of entry among paramyxoviruses

Abstract

The Paramyxoviridae family includes many viruses that are pathogenic in humans, including parainfluenza viruses, measles virus, respiratory syncytial virus, and the emerging zoonotic Henipaviruses. No effective treatments are currently available for these viruses, and there is a need for efficient antiviral therapies. Paramyxoviruses enter the target cell by binding to a cell surface receptor and then fusing the viral envelope with the target cell membrane, allowing the release of the viral genome into the cytoplasm. Blockage of these crucial steps prevents infection and disease. Binding and fusion are driven by two virus-encoded glycoproteins, the receptor-binding protein and the fusion protein, that together form the viral "fusion machinery." The development of efficient antiviral drugs requires a deeper understanding of the mechanism of action of the Paramyxoviridae fusion machinery, which is still controversial. Here, we review recent structural and functional data on these proteins and the current understanding of the mechanism of the paramyxovirus cell entry process.

Keywords: Fusion machinery; Fusion protein; Paramyxoviridae; Receptor-binding protein; Viral entry.

Figure 1. World distribution of major paramyxoviruses

Paramyxoviruses are found on every continent. Henipa- and Henipa-like viruses have been found in Oceania, Asia, Africa and South America, but human infections have only been reported in Oceania and South-East Asia. Data gathered from Enders et al., Ganar et al., Croser et al. the World Health Organization, the World Organization for Animal Health, and recent studies. Abbreviations are as in Table 1.

Figure 2. Schematic representation of the common structure of Paramyxoviruses

Paramyxoviridae are enveloped viruses. They contain single-stranded negative RNA coated with nucleocapsid (N) protein as well as a large (L) protein and a phosphoprotein (P) that carries out polymerase activity. The matrix (M) protein lines the viral lipid bilayer. The two viral glycoproteins -- hemagglutinin-neuraminidase (HN)/ hemagglutinin (H)/ glycoprotein (G) and fusion (F) -- protude from the viral membrane.

Figure 3. Structure of the Newcastle disease virus hemagglutinin-neuraminidase protein

3.1 Side view of the crystal structure of the tetramerized NDV-HN ectodomain showing the stalk and the globular domains of each monomer. Each color represents one monomer of the receptor-binding protein. One dimer is composed of green and yellow monomers, the other of red and blue monomers. (PDB ID: 3T1E; Yuan et al.). 3.2 Top view of the crystal structure of the tetramerized NDV-HN ectodomain, showing sialic acid binding sites I and II. Each monomer bears a site I and a site II. (PDB ID: 3T1E; Yuan et al.) 3.3 Schematic representation of the domains of NDV HN.

Figure 3. Structure of the Newcastle disease virus hemagglutinin-neuraminidase protein

3.1 Side view of the crystal structure of the tetramerized NDV-HN ectodomain showing the stalk and the globular domains of each monomer. Each color represents one monomer of the receptor-binding protein. One dimer is composed of green and yellow monomers, the other of red and blue monomers. (PDB ID: 3T1E; Yuan et al.). 3.2 Top view of the crystal structure of the tetramerized NDV-HN ectodomain, showing sialic acid binding sites I and II. Each monomer bears a site I and a site II. (PDB ID: 3T1E; Yuan et al.) 3.3 Schematic representation of the domains of NDV HN.

Figure 4. Structure of the paramyxovirus fusion protein

4.1 Crystal structure of the pre-fusion state of the trimeric fusion protein of PIV5 showing the fusion peptide (purple) in the hydrophobic pocket formed by ae hydrophobic domain (deep green), the HRN domain (deep blue) and the F₂ sub-unit (yellow). (PDB ID: 4GIP; Welch et al.). 4.2 Crystal structure of the post-fusion state of the fusion protein of HPIV3 showing the 6-helix bundle structure formed by the HRN (deep blue) and HRC (red) domains interacting together. (PBDB ID: 1ZTM; Yin et al). 4.3 Schematic representation of the main domains of a monomer of the cleaved paramyxovirus fusion protein. HRC/HRN: Heptad Repeat C-/N-terminal domain.

Figure 4. Structure of the paramyxovirus fusion protein

4.1 Crystal structure of the pre-fusion state of the trimeric fusion protein of PIV5 showing the fusion peptide (purple) in the hydrophobic pocket formed by ae hydrophobic domain (deep green), the HRN domain (deep blue) and the F₂ sub-unit (yellow). (PDB ID: 4GIP; Welch et al.). 4.2 Crystal structure of the post-fusion state of the fusion protein of HPIV3 showing the 6-helix bundle structure formed by the HRN (deep blue) and HRC (red) domains interacting together. (PBDB ID: 1ZTM; Yin et al). 4.3 Schematic representation of the main domains of a monomer of the cleaved paramyxovirus fusion protein. HRC/HRN: Heptad Repeat C-/N-terminal domain.

Figure 4. Structure of the paramyxovirus fusion protein

4.1 Crystal structure of the pre-fusion state of the trimeric fusion protein of PIV5 showing the fusion peptide (purple) in the hydrophobic pocket formed by ae hydrophobic domain (deep green), the HRN domain (deep blue) and the F₂ sub-unit (yellow). (PDB ID: 4GIP; Welch et al.). 4.2 Crystal structure of the post-fusion state of the fusion protein of HPIV3 showing the 6-helix bundle structure formed by the HRN (deep blue) and HRC (red) domains interacting together. (PBDB ID: 1ZTM; Yin et al). 4.3 Schematic representation of the main domains of a monomer of the cleaved paramyxovirus fusion protein. HRC/HRN: Heptad Repeat C-/N-terminal domain.

Figure 5. Unified model for Paramyxoviridae fusion process

See text for description. Pink: HRN domain and fusion peptide. HRC/HRN: Heptad Repeat C-/N-terminal domain.