The Measles Virus Hemagglutinin β-Propeller Head β4-β5 Hydrophobic Groove Governs Functional Interactions with Nectin-4 and CD46 but Not Those with the Signaling Lymphocytic Activation Molecule

Abstract

Measles virus (MV), which belongs to the family Paramyxoviridae within the order Mononegavirales (1), may be the most contagious aerosol-transmitted virus circulating in human populations (2). In 2010, about 139,000 people died from secondary infections due to MV-induced immune suppression (3, 4). While a worldwide vaccination campaign aiming at eradication is ongoing (5), diminishing vaccine coverage in the United States and Europe has caused a rebound of measles cases in 2011, threatening the feasibility of eradication by 2020 (6).MV infection starts in alveolar macrophages and dendritic cells of the airways, which transport the virus to the lymphoid organs (7,8). MV then replicates rapidly and extensively in local lymph nodes and primary lymphatic organs. Infected immune cells circulate through the body and can transmit the infection to the respiratory epithelium, from where the virus is shed through coughing and sneezing (9-12).Wild-type MV sequentially infects immune cells through the signaling lymphocytic activation molecule (SLAM; CD150) (13) and epithelial cells through the adherens junction protein nectin-4, also known as poliovirus receptor-like 4 (PVRL4) (12,14,15). In addition, the MV vaccine strain uses the ubiquitous regulator of complement activation membrane cofactor protein (MCP; CD46) as a receptor (16,17). MV attachment to its three receptors occurs through hemagglutinin (H), a type II transmembrane glycoprotein (18). The H ectodomain is composed of a tetrameric membrane-proximal stalk topped by four six-bladed ␤-propeller globular heads (19). Receptor attachment to the H globular head can trigger refolding of the trimeric fusion (F) protein and cell entry.While H-to-F signal transmission is only beginning to be understood (20-24), the molecular basis of the interactions of the receptors with H is better characterized. Initial functional analyses identified different H residues important for the interactions with the three receptors (11,(25)(26)(27)(28)(29)(30)(31). These studies were recently complemented by crystal structures of H in complex with CD46, SLAM, and nectin-4 (32-34). The SLAM (32) and CD46 (33) costructures are based on slightly different vaccine lineage H proteins, while the nectin-4 costructure (34) is based on a wild-type H protein differing by more than 17 residues from the other two proteins. Comparative analyses of the three costructures (34) concluded that a hydrophobic pocket centered in the ␤4-␤5 groove is involved in binding of all receptors. On the other hand, previous functional analyses revealed differences between the interactions of H and individual receptors (11,(25)(26)(27)(28)(29)(30)(31). Based on the recent identification of nectin-4 as an epithelial receptor, based on the availability of new cell lines and specific reagents for all three receptors, and focusing on the overlap of the structural footprints of the receptors, we reexamined here the functional interactions of H with its three cellular partners. We used a vaccine lineage H protein, allowing direct...

The Nectin-4/Afadin Protein Complex and Intercellular Membrane Pores Contribute to Rapid Spread of Measles Virus in Primary Human Airway Epithelia

“…All four paramyxoviruses considered here enter cells by fusion at the plasma membrane at a neutral pH; however, the attachment proteins of respiroviruses and rubulaviruses bind ubiquitous sialic acids, while the attachment proteins of morbilliviruses bind the receptors SLAM and nectin-4 (18). Tissue-specific expression of SLAM and nectin-4 appears to be a main determinant of MV tropism (18,19), and the biological properties of these receptors may also facilitate steps of the pathogenic process.…”

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

“…Since receptor engagement promotes F's fusion activity, constant receptor engagement may permit an HN/F pair to resist inhibition by fusion-inhibitory peptides (60). Interaction of measles virus H with its receptor is dynamic, with on and off events between individual molecules (61), while the affinity of the overall complex is maintained (27,62). We hypothesized that reducing the number of MV H attachment proteins interacting with CD150 receptor molecules would increase the fusion inhibition efficacy of peptides.…”

Ablation of Nectin4 Binding Compromises CD46 Usage by a Hybrid Vesicular Stomatitis Virus/Measles Virus

“…Recent structural studies revealed that all three receptors of MV bind close to a hydrophobic groove located between blades 4 and 5 (␤4-␤5 groove) of the measles H protein ␤-propeller head (32-34). Mateo et al recently reported that there is a strong overlap between the functional footprints of nectin4 and CD46 but not SLAM (35). Based on these studies, it is thus not surprising that ablation of nectin4 binding in VSVFH would result in a significant compromise in H usage of CD46 and impairment of its oncolysis of human cancer cells.…”