Paramyxovirus Entry

Abstract

The family Paramyxoviridae consists of a group of large, enveloped, negative-sense, single-stranded RNA viruses and contains many important human and animal pathogens. Molecular and biochemical characterization over the past decade has revealed an extraordinary breadth of biological diversity among this family of viruses. Like all enveloped viruses, paramyxoviruses must fuse their membrane with that of a receptive host cell as a prerequisite for viral entry and infection. Unlike most other enveloped viruses, the vast majority of paramyxoviruses contain two distinct membrane-anchored glycoproteins to mediate the attachment, membrane fusion and particle entry stages of host cell infection. The attachment glycoprotein is required for virion attachment and the fusion glycoprotein is directly involved in facilitating the merger of the viral and host cell membranes. Here we detail important functional, biochemical and structural features of the attachment and fusion glycoproteins from a variety of family members. Specifically, the three different classes of attachment glycoproteins are discussed, including receptor binding preference, their overall structure and fusion promotion activities. Recently solved atomic structures of certain attachment glycoproteins are summarized, and how they relate to both receptor binding and fusion mechanisms are described. For the fusion glycoprotein, specific structural domains and their proposed role in mediating membrane merger are illustrated, highlighting the important features of protease cleavage and associated tropism and virulence. The crystal structure solutions of both an uncleaved and a cleavage-activated metastable F are also described with emphasis on how small conformational changes can provide the necessary energy to mediate membrane fusion. Finally, the different proposed fusion models are reviewed, featuring recent experimental findings that speculate how the attachment and fusion glycoproteins work in concert to mediate virus entry.

Probing the paramyxovirus fusion (F) protein-refolding event from pre- to postfusion by oxidative footprinting

“…Embedded in the viral envelope are the viral spike glycoproteins necessary for receptor binding and fusion with a target cell. The receptor-binding and fusion activities are carried out by a variable attachment protein, known as "HN," "H," or "G" protein, and a more conserved fusion (F) protein, respectively (3)(4)(5). Coexpression of HN, H, or G and the F protein in the same cell is required to activate the F protein, and coimmunoprecipitation data indicate F and HN, H, or G interact physically through the HN, H, or G stalk region (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

Measles Virus Fusion Machinery Activated by Sialic Acid Binding Globular Domain

“…The F protein then undergoes a series of conformational changes that permit it to insert into the target membrane and merge the viral and cell membranes (reviewed in references 6 and 7). The interaction between the two envelope glycoproteins and the subsequent events that lead to fusion are critical to the entry process (8)(9)(10)(11)(12).…”

Structural characterisation of glycosylation of paramyxovirus attachment and fusion proteins by mass spectrometry

“…With respect to viral infection, glycosylation of viral surface proteins has been implicated in attachment and entry, induction of immune responses and evasion of host-immune responses (37)(38)(39)(40).…”

“…These proteins bind to host cells via specific carbohydrate residues or host cell proteins and may also facilitate viral entry (37,64). The matrix protein is found on the inner surface of the lipid bilayer, stabilising the virion structure and directing assembly and budding.…”

“…Moreover, the crystal structure of F from HeV reveals that the conformation of the fusion peptide adjacent to the cleavage site differs to PIV5, likely due to substrate requirements of the enzymes that cleave each protein (329). There is also a greater reliance on the attachment proteins of Paramyxovirinae for fusion promotion than in the Pneumovirinae subfamily (37). Even within Paramyxovirinae different models of fusion activation are predicted (39,55).…”