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The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein

View Article: PubMed Central - PubMed

ABSTRACT

The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces.

No MeSH data available.


Summary of the principal residues contained in the β4, β5, and β6 regions in the head of the H protein involved in binding to its receptors. (A) CD46; (B) Nectin-4; and (C) SLAMF1/SLAM cellular receptors. Amino acid residues involved in binding to CD46 are shown in red, those binding to Nectin-4 in yellow, and those interacting with SLAMF1/SLAM in blue; (D) Overview of receptor binding residues in H protein. Overlapping interacting H residues (F483, Y541, Y543) for CD46 and Nectin-4 are shown in orange. Reprinted with permission from the American Society of Microbiology Journals: Mateo, M.; Navaratnarajah, C.K.; Syed, S.; Cattaneo, R. J. Virol.2013, 87, 9208–9216 [152].
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viruses-08-00250-f011: Summary of the principal residues contained in the β4, β5, and β6 regions in the head of the H protein involved in binding to its receptors. (A) CD46; (B) Nectin-4; and (C) SLAMF1/SLAM cellular receptors. Amino acid residues involved in binding to CD46 are shown in red, those binding to Nectin-4 in yellow, and those interacting with SLAMF1/SLAM in blue; (D) Overview of receptor binding residues in H protein. Overlapping interacting H residues (F483, Y541, Y543) for CD46 and Nectin-4 are shown in orange. Reprinted with permission from the American Society of Microbiology Journals: Mateo, M.; Navaratnarajah, C.K.; Syed, S.; Cattaneo, R. J. Virol.2013, 87, 9208–9216 [152].

Mentions: Using a receptor-dependent fusion assay and site-specific mutations of residues making up the putative receptor binding site on the H protein, critical residues for binding to CD46, Nectin-4, and SLAMF1 were mapped [152]. F484, Y541, and Y543 were important for binding to all three receptors. Other mutations on H were used to discriminate binding regions to the three different receptors. I194S, D530A and R533A abolished binding to SLAMF1. V451S, L464S, Y481S, K488A, T498A, and L500S reduced CD46 binding. Finally, L482S, F483S, P497S, Y541A, and Y543A blocked binding to Nectin-4. The Y543A mutation strongly reduces H binding to Nectin-4 and CD46 but has only a minimal effect on SLAMF1 binding and membrane fusion. This virus is unable to enter cells using CD46 and Nectin-4 but retains its ability to use SLAMF1 for entry. In an attempt to abrogate binding to Nectin-4 while still retaining to CD46 and SLAMF1, a L482S mutation was introduced into H. However, this change did not block Nectin-4 mediated cell entry but it did reduce cell-to-cell fusion. Based on the preceding data, Mateo et al. concluded that there was a strong overlap between the footprints of Nectin-4 and CD46 binding but not that of SLAMF1. The authors reported that Nectin-4 and CD46 interact functionally with the H protein β4–β5 hydrophobic groove, while SLAMF1 simply covers it. The authors suggested that the hydrophobic groove is not relevant for entry using SLAMF1, which interacts primarily with the β5 and β6 propeller blades of H. They also suggest that the CD46 binding site in the H protein of the measles vaccine strain may have evolved from the Nectin-4 binding site through minor changes. The results of the preceding mutational analysis of MeV H protein are summarized in Figure 11. Mutational analysis of the canonical adhesive interface of the V domain of Nectin-4 showed that the FG loop protrudes into the H-protein hydrophobic groove and that its BC loop covers the groove and helps stabilize the complex [153]. The residues D60, V62, and G63 are key residues supporting contacts by the BC loop and mutations in amino acids 61–64 of the V domain abrogate binding to H protein. A G63E substitution found in porcine Nectin-4 blocks the interaction between Nectin-4 and H protein, and helps determine species specific interaction of the virus. Recently, Takeda’s group showed that vaccine strains of MeV could use a Nectin-4 homologue in chick embryo fibroblasts as a receptor [154]. This homologue contained well-conserved FG and BC loop motifs, but the non-essential C’C’’ loop varied considerably from mammalian Nectin-4 molecules.


The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein
Summary of the principal residues contained in the β4, β5, and β6 regions in the head of the H protein involved in binding to its receptors. (A) CD46; (B) Nectin-4; and (C) SLAMF1/SLAM cellular receptors. Amino acid residues involved in binding to CD46 are shown in red, those binding to Nectin-4 in yellow, and those interacting with SLAMF1/SLAM in blue; (D) Overview of receptor binding residues in H protein. Overlapping interacting H residues (F483, Y541, Y543) for CD46 and Nectin-4 are shown in orange. Reprinted with permission from the American Society of Microbiology Journals: Mateo, M.; Navaratnarajah, C.K.; Syed, S.; Cattaneo, R. J. Virol.2013, 87, 9208–9216 [152].
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5035964&req=5

viruses-08-00250-f011: Summary of the principal residues contained in the β4, β5, and β6 regions in the head of the H protein involved in binding to its receptors. (A) CD46; (B) Nectin-4; and (C) SLAMF1/SLAM cellular receptors. Amino acid residues involved in binding to CD46 are shown in red, those binding to Nectin-4 in yellow, and those interacting with SLAMF1/SLAM in blue; (D) Overview of receptor binding residues in H protein. Overlapping interacting H residues (F483, Y541, Y543) for CD46 and Nectin-4 are shown in orange. Reprinted with permission from the American Society of Microbiology Journals: Mateo, M.; Navaratnarajah, C.K.; Syed, S.; Cattaneo, R. J. Virol.2013, 87, 9208–9216 [152].
Mentions: Using a receptor-dependent fusion assay and site-specific mutations of residues making up the putative receptor binding site on the H protein, critical residues for binding to CD46, Nectin-4, and SLAMF1 were mapped [152]. F484, Y541, and Y543 were important for binding to all three receptors. Other mutations on H were used to discriminate binding regions to the three different receptors. I194S, D530A and R533A abolished binding to SLAMF1. V451S, L464S, Y481S, K488A, T498A, and L500S reduced CD46 binding. Finally, L482S, F483S, P497S, Y541A, and Y543A blocked binding to Nectin-4. The Y543A mutation strongly reduces H binding to Nectin-4 and CD46 but has only a minimal effect on SLAMF1 binding and membrane fusion. This virus is unable to enter cells using CD46 and Nectin-4 but retains its ability to use SLAMF1 for entry. In an attempt to abrogate binding to Nectin-4 while still retaining to CD46 and SLAMF1, a L482S mutation was introduced into H. However, this change did not block Nectin-4 mediated cell entry but it did reduce cell-to-cell fusion. Based on the preceding data, Mateo et al. concluded that there was a strong overlap between the footprints of Nectin-4 and CD46 binding but not that of SLAMF1. The authors reported that Nectin-4 and CD46 interact functionally with the H protein β4–β5 hydrophobic groove, while SLAMF1 simply covers it. The authors suggested that the hydrophobic groove is not relevant for entry using SLAMF1, which interacts primarily with the β5 and β6 propeller blades of H. They also suggest that the CD46 binding site in the H protein of the measles vaccine strain may have evolved from the Nectin-4 binding site through minor changes. The results of the preceding mutational analysis of MeV H protein are summarized in Figure 11. Mutational analysis of the canonical adhesive interface of the V domain of Nectin-4 showed that the FG loop protrudes into the H-protein hydrophobic groove and that its BC loop covers the groove and helps stabilize the complex [153]. The residues D60, V62, and G63 are key residues supporting contacts by the BC loop and mutations in amino acids 61–64 of the V domain abrogate binding to H protein. A G63E substitution found in porcine Nectin-4 blocks the interaction between Nectin-4 and H protein, and helps determine species specific interaction of the virus. Recently, Takeda’s group showed that vaccine strains of MeV could use a Nectin-4 homologue in chick embryo fibroblasts as a receptor [154]. This homologue contained well-conserved FG and BC loop motifs, but the non-essential C’C’’ loop varied considerably from mammalian Nectin-4 molecules.

View Article: PubMed Central - PubMed

ABSTRACT

The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces.

No MeSH data available.