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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.


Related in: MedlinePlus

Interaction of CD46 with H dimer from the vaccine strain of MeV. (A) Schematic of membrane cofactor protein (MCP) or CD46. Protein is comprised of four short conserved regions (SCR1-SCR4), the Ser/Thr/Pro (STP) domain, transmembrane region, and two alternatively spliced cytoplasmic tails. MeV binds to SCR1 and SCR2 and complement components C3b, and C4b bind to SCR3 and SCR4. Sugars in SCR2 are important for MeV binding; (B) Structure of SCR1 and SCR2 domains of CD46 bound to H protein dimer head region. Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Santiago, C.; Celma, M.L.; Stehle, T.; Casasnovas, J.M. Nat. Struct. Mol. Biol. 2010, 17, 124–129 [73].
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viruses-08-00250-f004: Interaction of CD46 with H dimer from the vaccine strain of MeV. (A) Schematic of membrane cofactor protein (MCP) or CD46. Protein is comprised of four short conserved regions (SCR1-SCR4), the Ser/Thr/Pro (STP) domain, transmembrane region, and two alternatively spliced cytoplasmic tails. MeV binds to SCR1 and SCR2 and complement components C3b, and C4b bind to SCR3 and SCR4. Sugars in SCR2 are important for MeV binding; (B) Structure of SCR1 and SCR2 domains of CD46 bound to H protein dimer head region. Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Santiago, C.; Celma, M.L.; Stehle, T.; Casasnovas, J.M. Nat. Struct. Mol. Biol. 2010, 17, 124–129 [73].

Mentions: Structural analysis of the globular head of H protein complexed to SCR1 and SCR2 domains of CD46 revealed the interactions between the two proteins [73,74]. The crystal unit contained an H dimer bound to two CD46 molecules (Figure 4). A unique groove on the side of the β-propeller 4 domain of H engages residues in the SCR1 and SCR2 domains. Contact region 1 involves a Pro-Pro motif at the CD46 N-terminus that penetrates deep into a hydrophobic hole in the H protein. Important SCR1 residues for this interaction include Ile37, Pro38, Pro39, and Leu40 which form a plug that penetrates into the hydrophobic socket in H at the interface between blades β4 and β5. This protrusion is situated between the side chains of Leu464 and Leu500 in β4, and Tyr541 and Tyr543 of β5. Contact region 2 consists of the residues connecting SCR1 and SCR2. The Tyr481 hydroxyl of H forms a hydrogen bond with the carbonyl of Cys65 of CD46, and Gly546 of H introduces flexibility for high affinity binding. Contact region 3 involves almost the entire side of SCR2 where Tyr67 of CD46 aligns against Val451 of the H protein. In addition, the side chain of Tyr83 interacts with Tyr481 of H. The carbohydrate attached to Asn80 interacts with MeV H residue Lys488. The affinity of interaction between H from Edmonston MeV and CD46 was measured (Kd = 79 nM) [75].


The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein
Interaction of CD46 with H dimer from the vaccine strain of MeV. (A) Schematic of membrane cofactor protein (MCP) or CD46. Protein is comprised of four short conserved regions (SCR1-SCR4), the Ser/Thr/Pro (STP) domain, transmembrane region, and two alternatively spliced cytoplasmic tails. MeV binds to SCR1 and SCR2 and complement components C3b, and C4b bind to SCR3 and SCR4. Sugars in SCR2 are important for MeV binding; (B) Structure of SCR1 and SCR2 domains of CD46 bound to H protein dimer head region. Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Santiago, C.; Celma, M.L.; Stehle, T.; Casasnovas, J.M. Nat. Struct. Mol. Biol. 2010, 17, 124–129 [73].
© Copyright Policy
Related In: Results  -  Collection

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

viruses-08-00250-f004: Interaction of CD46 with H dimer from the vaccine strain of MeV. (A) Schematic of membrane cofactor protein (MCP) or CD46. Protein is comprised of four short conserved regions (SCR1-SCR4), the Ser/Thr/Pro (STP) domain, transmembrane region, and two alternatively spliced cytoplasmic tails. MeV binds to SCR1 and SCR2 and complement components C3b, and C4b bind to SCR3 and SCR4. Sugars in SCR2 are important for MeV binding; (B) Structure of SCR1 and SCR2 domains of CD46 bound to H protein dimer head region. Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Santiago, C.; Celma, M.L.; Stehle, T.; Casasnovas, J.M. Nat. Struct. Mol. Biol. 2010, 17, 124–129 [73].
Mentions: Structural analysis of the globular head of H protein complexed to SCR1 and SCR2 domains of CD46 revealed the interactions between the two proteins [73,74]. The crystal unit contained an H dimer bound to two CD46 molecules (Figure 4). A unique groove on the side of the β-propeller 4 domain of H engages residues in the SCR1 and SCR2 domains. Contact region 1 involves a Pro-Pro motif at the CD46 N-terminus that penetrates deep into a hydrophobic hole in the H protein. Important SCR1 residues for this interaction include Ile37, Pro38, Pro39, and Leu40 which form a plug that penetrates into the hydrophobic socket in H at the interface between blades β4 and β5. This protrusion is situated between the side chains of Leu464 and Leu500 in β4, and Tyr541 and Tyr543 of β5. Contact region 2 consists of the residues connecting SCR1 and SCR2. The Tyr481 hydroxyl of H forms a hydrogen bond with the carbonyl of Cys65 of CD46, and Gly546 of H introduces flexibility for high affinity binding. Contact region 3 involves almost the entire side of SCR2 where Tyr67 of CD46 aligns against Val451 of the H protein. In addition, the side chain of Tyr83 interacts with Tyr481 of H. The carbohydrate attached to Asn80 interacts with MeV H residue Lys488. The affinity of interaction between H from Edmonston MeV and CD46 was measured (Kd = 79 nM) [75].

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.


Related in: MedlinePlus