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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 Nectin-4. (A) Schematic of Nectin-4 showing the V and two C2 regions of the extracellular domain, the membrane spanning region, and the intracellular cytoplasmic tail; (B) Structure derived by X-ray crystallography showing heads of the H protein dimer interacting with the V regions of Nectin-4; (C) Structure of the head from β4 and β5 regions of monomeric H protein interacting with of the V domain of Nectin-4 (Nectin-4v). Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Zhang, X.; Lu, G.; Qi, J.; Li, Y.; He, Y.; Xu, X.; Shi, J.; Zhang, C.W.; Yan, J.; Gao, G.F. Nat. Struct. Mol. Biol.2013, 20, 67–72 [151].
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viruses-08-00250-f010: Structure of the head region from the H protein of MeV bound to the V region of Nectin-4. (A) Schematic of Nectin-4 showing the V and two C2 regions of the extracellular domain, the membrane spanning region, and the intracellular cytoplasmic tail; (B) Structure derived by X-ray crystallography showing heads of the H protein dimer interacting with the V regions of Nectin-4; (C) Structure of the head from β4 and β5 regions of monomeric H protein interacting with of the V domain of Nectin-4 (Nectin-4v). Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Zhang, X.; Lu, G.; Qi, J.; Li, Y.; He, Y.; Xu, X.; Shi, J.; Zhang, C.W.; Yan, J.; Gao, G.F. Nat. Struct. Mol. Biol.2013, 20, 67–72 [151].

Mentions: Within a year of identification of the MeV epithelial receptor, the molecular structure of H protein bound to the V region of nectin-4 (Nectin-4v) was reported [151]. H protein derived from wild-type strain IC-B folded into the characteristic six-bladed β-propeller with each blade comprised of a four-stranded β-sheet. The extra N-glycosylation site at position 416 of the H protein was clearly observed. The V domain adopted its characteristic immunoglobulin fold (IgV) and inserted into the concave hydrophobic side groove formed by the β4 and β5 blades (Figure 10). Site I on the V domain conferred strong stabilization through hydrophobic interactions. Residues Ser99–Phe106 of Nectin-4v interact with MeV H residues Tyr524, Leu526, Tyr541, and Tyr543 of the β5 blade on one side and Pro458, Met459, Leu462-Gly 465, Leu 482, and Phe 483 of the β4 blade. Phe101–Gly104 of Nectin-4v has a pivotal role in MeV H protein interaction. Site II involves Gln30, Gly32, and Gln33 of Nectin-4v which interact with Thr 498, Tyr499 and Asp505 in the intervening loop between blades 4 and 5 of MEV H. Finally, site III consists of His52–Tyr55 of Nectin-4v contacting H protein residues Ly387–Ly389 and Gln 391 in the β3 blade and Tyr499 and Leu500 in the β4–β5 loop. The Kd binding of H with Nectin-4 is 20 nM [138].


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 Nectin-4. (A) Schematic of Nectin-4 showing the V and two C2 regions of the extracellular domain, the membrane spanning region, and the intracellular cytoplasmic tail; (B) Structure derived by X-ray crystallography showing heads of the H protein dimer interacting with the V regions of Nectin-4; (C) Structure of the head from β4 and β5 regions of monomeric H protein interacting with of the V domain of Nectin-4 (Nectin-4v). Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Zhang, X.; Lu, G.; Qi, J.; Li, Y.; He, Y.; Xu, X.; Shi, J.; Zhang, C.W.; Yan, J.; Gao, G.F. Nat. Struct. Mol. Biol.2013, 20, 67–72 [151].
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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viruses-08-00250-f010: Structure of the head region from the H protein of MeV bound to the V region of Nectin-4. (A) Schematic of Nectin-4 showing the V and two C2 regions of the extracellular domain, the membrane spanning region, and the intracellular cytoplasmic tail; (B) Structure derived by X-ray crystallography showing heads of the H protein dimer interacting with the V regions of Nectin-4; (C) Structure of the head from β4 and β5 regions of monomeric H protein interacting with of the V domain of Nectin-4 (Nectin-4v). Adapted by permission from the Nature Publishing Group, Macmillan Publishers Ltd.: Zhang, X.; Lu, G.; Qi, J.; Li, Y.; He, Y.; Xu, X.; Shi, J.; Zhang, C.W.; Yan, J.; Gao, G.F. Nat. Struct. Mol. Biol.2013, 20, 67–72 [151].
Mentions: Within a year of identification of the MeV epithelial receptor, the molecular structure of H protein bound to the V region of nectin-4 (Nectin-4v) was reported [151]. H protein derived from wild-type strain IC-B folded into the characteristic six-bladed β-propeller with each blade comprised of a four-stranded β-sheet. The extra N-glycosylation site at position 416 of the H protein was clearly observed. The V domain adopted its characteristic immunoglobulin fold (IgV) and inserted into the concave hydrophobic side groove formed by the β4 and β5 blades (Figure 10). Site I on the V domain conferred strong stabilization through hydrophobic interactions. Residues Ser99–Phe106 of Nectin-4v interact with MeV H residues Tyr524, Leu526, Tyr541, and Tyr543 of the β5 blade on one side and Pro458, Met459, Leu462-Gly 465, Leu 482, and Phe 483 of the β4 blade. Phe101–Gly104 of Nectin-4v has a pivotal role in MeV H protein interaction. Site II involves Gln30, Gly32, and Gln33 of Nectin-4v which interact with Thr 498, Tyr499 and Asp505 in the intervening loop between blades 4 and 5 of MEV H. Finally, site III consists of His52–Tyr55 of Nectin-4v contacting H protein residues Ly387–Ly389 and Gln 391 in the β3 blade and Tyr499 and Leu500 in the β4–β5 loop. The Kd binding of H with Nectin-4 is 20 nM [138].

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.