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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.


Structure of the head region from the H protein of MeV bound to the V region of SLAMF1. (A) Schematic of SLAMF1 showing the V and C2 regions of the extracellular domain, the membrane spanning region, and the intracellular region containing phosphotyrosine regions. Either of two cytoplasmic tails (1 or 2) may be present depending upon alternate splicing; (B) V region of SLAMF1 binding to β5 and β6 sheet regions from the head of the H protein viewed from the top; (C) Side view of V region of SLAMF1 binding to heads of the H dimer proteins; (D) V regions of four SLAMF1 molecules binding to the tetrameric H proteins. Panels B, C, and D adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Hashiguchi, T.; Ose, T., Kubota, M.; Maita, N.; Kamishikiryo, J.; Maenaka, K.; Yanagi, Y. Nat. Struct. Mol. Biol.2011, 18, 135–141 [102].
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viruses-08-00250-f006: Structure of the head region from the H protein of MeV bound to the V region of SLAMF1. (A) Schematic of SLAMF1 showing the V and C2 regions of the extracellular domain, the membrane spanning region, and the intracellular region containing phosphotyrosine regions. Either of two cytoplasmic tails (1 or 2) may be present depending upon alternate splicing; (B) V region of SLAMF1 binding to β5 and β6 sheet regions from the head of the H protein viewed from the top; (C) Side view of V region of SLAMF1 binding to heads of the H dimer proteins; (D) V regions of four SLAMF1 molecules binding to the tetrameric H proteins. Panels B, C, and D adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Hashiguchi, T.; Ose, T., Kubota, M.; Maita, N.; Kamishikiryo, J.; Maenaka, K.; Yanagi, Y. Nat. Struct. Mol. Biol.2011, 18, 135–141 [102].

Mentions: The published crystal structure of MeV H in complex with SLAMF1-V domain from Yanagi’s laboratory shows that β4–6 regions of H interact with the GFCC’C’’ region of the SLAMF1-V domain [101] (Figure 6). Salt bridges involving residues Asp530 and Arg 533 of H and Glu123 of SLAMF1-V play a major role in stabilizing the complex. An intermolecular β-sheet, comprised of residues Pro191–Arg196 (in β6) of H and residues Ser127–Phe131 of SLAMF1-V, further stabilizes the complex. The affinity of the MeV H and SLAMF1 interaction was measured (Kd = 80 nM) [75]. The MeV H protein exists as a dimer of two disulfide linked H proteins in the viral membrane to form a tetramer structure which interacts with a trimeric F protein [44]. Crystallography revealed two conformational states of these tetrameric structures (Form I and Form II). Both conformations have identical binding interactions with SLAMF1-V. Hashiguchi et al. suggest that Form II has an important role in membrane fusion that follows receptor binding. They suggest that the shift of the MeV H tetramer could trigger the conformational change in F protein required for membrane fusion [102]. A similar change can also be envisaged with CD46 binding. The Cattaneo group proposed a different model where two head domains in a MeV H dimer twist relative to each other upon receptor binding to trigger membrane fusion [12].


The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein
Structure of the head region from the H protein of MeV bound to the V region of SLAMF1. (A) Schematic of SLAMF1 showing the V and C2 regions of the extracellular domain, the membrane spanning region, and the intracellular region containing phosphotyrosine regions. Either of two cytoplasmic tails (1 or 2) may be present depending upon alternate splicing; (B) V region of SLAMF1 binding to β5 and β6 sheet regions from the head of the H protein viewed from the top; (C) Side view of V region of SLAMF1 binding to heads of the H dimer proteins; (D) V regions of four SLAMF1 molecules binding to the tetrameric H proteins. Panels B, C, and D adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Hashiguchi, T.; Ose, T., Kubota, M.; Maita, N.; Kamishikiryo, J.; Maenaka, K.; Yanagi, Y. Nat. Struct. Mol. Biol.2011, 18, 135–141 [102].
© Copyright Policy
Related In: Results  -  Collection

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

viruses-08-00250-f006: Structure of the head region from the H protein of MeV bound to the V region of SLAMF1. (A) Schematic of SLAMF1 showing the V and C2 regions of the extracellular domain, the membrane spanning region, and the intracellular region containing phosphotyrosine regions. Either of two cytoplasmic tails (1 or 2) may be present depending upon alternate splicing; (B) V region of SLAMF1 binding to β5 and β6 sheet regions from the head of the H protein viewed from the top; (C) Side view of V region of SLAMF1 binding to heads of the H dimer proteins; (D) V regions of four SLAMF1 molecules binding to the tetrameric H proteins. Panels B, C, and D adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Hashiguchi, T.; Ose, T., Kubota, M.; Maita, N.; Kamishikiryo, J.; Maenaka, K.; Yanagi, Y. Nat. Struct. Mol. Biol.2011, 18, 135–141 [102].
Mentions: The published crystal structure of MeV H in complex with SLAMF1-V domain from Yanagi’s laboratory shows that β4–6 regions of H interact with the GFCC’C’’ region of the SLAMF1-V domain [101] (Figure 6). Salt bridges involving residues Asp530 and Arg 533 of H and Glu123 of SLAMF1-V play a major role in stabilizing the complex. An intermolecular β-sheet, comprised of residues Pro191–Arg196 (in β6) of H and residues Ser127–Phe131 of SLAMF1-V, further stabilizes the complex. The affinity of the MeV H and SLAMF1 interaction was measured (Kd = 80 nM) [75]. The MeV H protein exists as a dimer of two disulfide linked H proteins in the viral membrane to form a tetramer structure which interacts with a trimeric F protein [44]. Crystallography revealed two conformational states of these tetrameric structures (Form I and Form II). Both conformations have identical binding interactions with SLAMF1-V. Hashiguchi et al. suggest that Form II has an important role in membrane fusion that follows receptor binding. They suggest that the shift of the MeV H tetramer could trigger the conformational change in F protein required for membrane fusion [102]. A similar change can also be envisaged with CD46 binding. The Cattaneo group proposed a different model where two head domains in a MeV H dimer twist relative to each other upon receptor binding to trigger membrane fusion [12].

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.