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The measles virus hemagglutinin ?-propeller head ?4-?5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not those with the signaling lymphocytic activation molecule.

ABSTRACT: Wild-type measles virus (MV) strains use the signaling lymphocytic activation molecule (SLAM; CD150) and the adherens junction protein nectin-4 (poliovirus receptor-like 4 [PVRL4]) as receptors. Vaccine MV strains have adapted to use ubiquitous membrane cofactor protein (MCP; CD46) in addition. Recently solved cocrystal structures of the MV attachment protein (hemagglutinin [H]) with each receptor indicate that all three bind close to a hydrophobic groove located between blades 4 and 5 (?4-?5 groove) of the H protein ?-propeller head. We used this structural information to focus our analysis of the functional footprints of the three receptors on vaccine MV H. We mutagenized this protein and tested the ability of individual mutants to support cell fusion through each receptor. The results highlighted a strong overlap between the functional footprints of nectin-4 and CD46 but not those of SLAM. A soluble form of nectin-4 abolished vaccine MV entry in nectin-4- and CD46-expressing cells but only reduced entry through SLAM. Analyses of the binding kinetics of an H mutant with the three receptors revealed that a single substitution in the ?4-?5 groove drastically reduced nectin-4 and CD46 binding while minimally altering SLAM binding. We also generated recombinant viruses and analyzed their infections in cells expressing individual receptors. Introduction of a single substitution into the hydrophobic pocket affected entry through both nectin-4 and CD46 but not through SLAM. Thus, while nectin-4 and CD46 interact functionally with the H protein ?4-?5 hydrophobic groove, SLAM merely covers it. This has implications for vaccine and antiviral strategies.

SUBMITTER: Mateo M

PROVIDER: S-EPMC3754078 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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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.

Mateo Mathieu M Navaratnarajah Chanakha K CK Syed Sabriya S Cattaneo Roberto R

Journal of virology 20130612 16

Wild-type measles virus (MV) strains use the signaling lymphocytic activation molecule (SLAM; CD150) and the adherens junction protein nectin-4 (poliovirus receptor-like 4 [PVRL4]) as receptors. Vaccine MV strains have adapted to use ubiquitous membrane cofactor protein (MCP; CD46) in addition. Recently solved cocrystal structures of the MV attachment protein (hemagglutinin [H]) with each receptor indicate that all three bind close to a hydrophobic groove located between blades 4 and 5 (β4-β5 gr ...[more]

PMID: 23760251

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Project description:We analyzed the roles of the individual measles virus (MV) surface glycoproteins in mediating functional and structural interactions with human CD46, the primary MV receptor. On one cell population, recombinant vaccinia virus vectors were used to produce the MV hemagglutinin (H) and fusion (F) glycoproteins. As fusion partner cells, various cell types were examined, without or with human CD46 (endogenous or recombinant vaccinia virus encoded). Fusion between the two cell populations was monitored by a quantitative reporter gene activation assay and by syncytium formation. MV glycoproteins promoted fusion with primate cells but not with nonprimate cells; recombinant CD46 rendered nonprimate cells competent for MV glycoprotein-mediated fusion. Markedly different fusion specificity was observed for another morbillivirus, canine distemper virus (CDV): recombinant CDV glycoproteins promoted fusion with primate and nonprimate cells independently of CD46. Fusion by the recombinant MV and CDV glycoproteins required coexpression of H plus F in either homologous or heterologous combinations. To assess the role of H versus F in determining the CD46 dependence of MV fusion, we examined the fusion specificities of cells producing heterologous glycoprotein combinations. The specificity of HMV plus FCDV paralleled that observed for the homologous MV glycoproteins: fusion occurred with primate cells but not with nonprimate cells unless they produced recombinant CD46. By contrast, the specificity of HCDV plus FMV paralleled that for the homologous CDV glycoproteins: fusion occurred with either primate or nonprimate cells with no dependence on CD46. Thus, for both MV and CDV, fusion specificity was determined by H. In particular, the results demonstrate a functional interaction between HMV and CD46. Flow cytometry and antibody coprecipitation studies provided a structural correlate to this functional interaction: CD46 formed a molecular complex with HMV but not with FMV or with either CDV glycoprotein. These results highlight the critical role of the H glycoprotein in determining MV specificity for CD46-positive cells.

Dataset Information

The measles virus hemagglutinin ?-propeller head ?4-?5 hydrophobic groove governs functional interactions with nectin-4 and CD46 but not those with the signaling lymphocytic activation molecule.

Publications

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.

Similar Datasets

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