Paramyxoviruses: different receptors – different mechanisms of fusion

Abstract

Paramyxovirus-mediated membrane fusion usually requires an interaction between the viralattachment and -fusion proteins. The mechanism by which this interaction regulates fusion differs between paramyxoviruses that bind to sialic acid-containing receptors and those that recognize specific proteins. The recently solved structure of the globular head of the measles virus hemagglutinin suggests that this difference might be related to the location of the receptor-binding sites on the attachment proteins of the two classes of paramyxoviruses. Paramyxoviruses use different receptorsThe Paramyxoviruses are enveloped, negative-stranded RNA viruses, each of which contains two surface glycoproteins, an attachment protein and a fusion (F) protein [1]. The most common type of paramyxovirus attachment protein, called the hemagglutinin-neuraminidase (HN), found on viruses, such as Newcastle disease virus (NDV), human parainfluenza virus 3 (hPIV3) and parainfluenza virus 5 (PIV5) (known formerly as simian virus 5), recognizes the ubiquitous sugar, sialic acid, on cell-surface moieties and has the ability to cleave the same moiety by virtue of its neuraminidase (NA) activity [1]. The structures of the globular heads of all of the above HN proteins [2-4] reveal a conserved β-sheet propeller motif, as identified originally in the influenza virus NA protein [5], but with a sialic acid-binding site on each monomer of the homotetramer that can mediate both receptor binding and NA (hereafter referred to as the NA site). A second binding site was identified subsequently in NDV HN [6] and has been postulated in hPIV3 HN [7]. Unlike HN, the hemagglutinin (H) of measles virus (MV) lacks NA and recognizes specific proteins. Although both wild-type and vaccine strains recognize signal lymphocyte-activating molecule (SLAM), vaccine strains also use CD46 as a receptor [8][9][10][11]. The recent publication by two groups of the structure of the globular domain of the MV H protein [12,13] provides our first look at a paramyxovirus attachment protein that binds to a specific protein receptor, revealing differences from the HN structures that might be related to the differences in the mechanisms by which these viruses mediate fusion. Location of receptor-binding sites on paramyxovirus attachment proteinsThe NA site in the various HN proteins is highly conserved and located in a pocket a short distance from the dimer interface (Figure 1a). The second sialic acid-binding site in NDV HN spans the membrane-distal end of the dimer interface and is composed of residues from both

Probing the Spatial Organization of Measles Virus Fusion Complexes

“…The stalk domains of several paramyxovirus HN proteins have been implicated in mediating specificity for their homotypic F proteins (18,20,43,63,70,72). We have found that this extends to MeV and canine distemper virus H and, thus, to paramyxovirinae recognizing proteinaceous receptors (36), supporting the general hypothesis that F-interacting residues may reside in the stalk region of the attachment protein (30,78).…”

Identification of a Region in the Stalk Domain of the Nipah Virus Receptor Binding Protein That Is Critical for Fusion Activation

“…The role of the receptor binding protein has been considered to be mainly repressive for viruses such as measles virus and NiV, where clamping the F protein prevents it from assuming a postfusion structure before the virus engages its proteinaceous receptor (10,12,36,47,(57)(58)(59)(60)(61). In the case of sialic acid binding receptor binding paramyxoviruses, such as HPIV and NDV, en- viruses engage receptor, the receptor binding proteins stabilize the F protein to prevent premature activation, and the switch to an active role in triggering the F protein to fuse occurs upon receptor engagement (17).…”

Role of the Two Sialic Acid Binding Sites on the Newcastle Disease Virus HN Protein in Triggering the Interaction with the F Protein Required for the Promotion of Fusion

“…However, receptor binding and fusion are mediated by two different glycoproteins, the attachment and fusion (F) proteins, respectively, requiring a mechanism by which the two processes can be linked. This is accomplished by a virus-specific interaction between the two proteins (9,10,13,19).…”

“…However, receptor binding and fusion are mediated by two different glycoproteins, the attachment and fusion (F) proteins, respectively, requiring a mechanism by which the two processes can be linked. This is accomplished by a virus-specific interaction between the two proteins (9,10,13,19).The ectodomain of paramyxovirus attachment proteins, including the NDV hemagglutinin-neuraminidase (HN), consists of a long stalk connected to a terminal globular domain (12). Whereas the HN globular domain mediates binding to sialic acid receptors, the stalk mediates the interaction with the homologous F protein (5,15,16).…”