Abstract
Measles virus, a major cause of childhood morbidity and mortality worldwide, predominantly infects immune cells using signaling lymphocyte activation molecule (SLAM) as a cellular receptor. Here we present crystal structures of measles virus hemagglutinin (MV-H), the receptor-binding glycoprotein, in complex with SLAM. The MV-H head domain binds to a β-sheet of the membrane-distal ectodomain of SLAM using the side of its β-propeller fold. This is distinct from attachment proteins of other paramyxoviruses that bind receptors using the top of their β-propeller. The structure provides templates for antiviral drug design, an explanation for the effectiveness of the measles virus vaccine, and a model of the homophilic SLAM-SLAM interaction involved in immune modulations. Notably, the crystal structures obtained show two forms of the MV-H–SLAM tetrameric assembly (dimer of dimers), which may have implications for the mechanism of fusion triggering.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bryce, J., Boschi-Pinto, C., Shibuya, K. & Black, R.E. WHO estimates of the causes of death in children. Lancet 365, 1147–1152 (2005).
Moss, W.J. & Griffin, D.E. Global measles elimination. Nat. Rev. Microbiol. 4, 900–908 (2006).
Griffin, D.E. in Fields Virology (eds. Knipe, D.M. et al.) 1551–1585 (Lippincott Williams & Wilkins, Philadelphia, 2007).
Harrison, S.C. Viral membrane fusion. Nat. Struct. Mol. Biol. 15, 690–698 (2008).
Lamb, R.A. & Parks, G.D. in Fields Virology (eds. Knipe, D.M. et al.) 1449–1496 (Lippincott Williams & Wilkins, Philadelphia, 2007).
Iorio, R.M. & Mahon, P.J. Paramyxoviruses: different receptors—different mechanisms of fusion. Trends Microbiol. 16, 135–137 (2008).
Smith, E.C., Popa, A., Chang, A., Masante, C. & Dutch, R.E. Viral entry mechanisms: the increasing diversity of paramyxovirus entry. FEBS J. 276, 7217–7227 (2009).
Connolly, S.A., Leser, G.P., Jardetzky, T.S. & Lamb, R.A. Bimolecular complementation of paramyxovirus fusion and hemagglutinin-neuraminidase proteins enhances fusion: implications for the mechanism of fusion triggering. J. Virol. 83, 10857–10868 (2009).
Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897 (2000).
Yanagi, Y., Takeda, M., Ohno, S. & Hashiguchi, T. Measles virus receptors. Curr. Top. Microbiol. Immunol. 329, 13–30 (2009).
Cocks, B.G. et al. A novel receptor involved in T-cell activation. Nature 376, 260–263 (1995).
Schwartzberg, P.L., Mueller, K.L., Qi, H. & Cannons, J.L. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat. Rev. Immunol. 9, 39–46 (2009).
Kiel, M.J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).
Mavaddat, N. et al. Signaling lymphocytic activation molecule (CDw150) Is homophilic but self-associates with very low affinity. J. Biol. Chem. 275, 28100–28109 (2000).
Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993).
Dörig, R.E., Marcil, A., Chopra, A. & Richardson, C.D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295–305 (1993).
Manchester, M., Liszewski, M.K., Atkinson, J.P. & Oldstone, M.B. Multiple isoforms of CD46 (membrane cofactor protein) serve as receptors for measles virus. Proc. Natl. Acad. Sci. USA 91, 2161–2165 (1994).
Takeda, M. et al. A human lung carcinoma cell line supports efficient measles virus growth and syncytium formation via a SLAM- and CD46-independent mechanism. J. Virol. 81, 12091–12096 (2007).
Tahara, M. et al. Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin. J. Virol. 82, 4630–4637 (2008).
Leonard, V.H. et al. Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J. Clin. Invest. 118, 2448–2458 (2008).
Hashiguchi, T. et al. Crystal structure of measles virus hemagglutinin provides insight into effective vaccines. Proc. Natl. Acad. Sci. USA 104, 19535–19540 (2007).
Colf, L.A., Juo, Z.S. & Garcia, K.C. Structure of the measles virus hemagglutinin. Nat. Struct. Mol. Biol. 14, 1227–1228 (2007).
Santiago, C., Celma, M.L., Stehle, T. & Casasnovas, J.M. Structure of the measles virus hemagglutinin bound to the CD46 receptor. Nat. Struct. Mol. Biol. 17, 124–129 (2010).
Ono, N., Tatsuo, H., Tanaka, K., Minagawa, H. & Yanagi, Y. V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor. J. Virol. 75, 1594–1600 (2001).
Reeves, P.J., Callewaert, N., Contreras, R. & Khorana, H.G. Structure and function in rhodopsin: high-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line. Proc. Natl. Acad. Sci. USA 99, 13419–13424 (2002).
Evans, E.J. et al. Crystal structure and binding properties of the CD2 and CD244 (2B4)-binding protein, CD48. J. Biol. Chem. 281, 29309–29320 (2006).
Massé, N. et al. Measles virus (MV) hemagglutinin: evidence that attachment sites for MV receptors SLAM and CD46 overlap on the globular head. J. Virol. 78, 9051–9063 (2004).
Vongpunsawad, S., Oezgun, N., Braun, W. & Cattaneo, R. Selectively receptor-blind measles viruses: Identification of residues necessary for SLAM- or CD46-induced fusion and their localization on a new hemagglutinin structural model. J. Virol. 78, 302–313 (2004).
Yuan, P. et al. Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose. Structure 13, 803–815 (2005).
Bowden, T.A. et al. Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2. Nat. Struct. Mol. Biol. 15, 567–572 (2008).
Xu, K. et al. Host cell recognition by the henipaviruses: crystal structures of the Nipah G attachment glycoprotein and its complex with ephrin-B3. Proc. Natl. Acad. Sci. USA 105, 9953–9958 (2008).
Varghese, J.N., Laver, W.G. & Colman, P.M. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 303, 35–40 (1983).
Burmeister, W.P., Ruigrok, R.W. & Cusack, S. The 2.2 A resolution crystal structure of influenza B neuraminidase and its complex with sialic acid. EMBO J. 11, 49–56 (1992).
Ohno, S., Seki, F., Ono, N. & Yanagi, Y. Histidine at position 61 and its adjacent amino acid residues are critical for the ability of SLAM (CD150) to act as a cellular receptor for measles virus. J. Gen. Virol. 84, 2381–2388 (2003).
Velikovsky, C.A. et al. Structure of natural killer receptor 2B4 bound to CD48 reveals basis for heterophilic recognition in signaling lymphocyte activation molecule family. Immunity 27, 572–584 (2007).
Zaitsev, V. et al. Second sialic acid binding site in Newcastle disease virus hemagglutinin-neuraminidase: implications for fusion. J. Virol. 78, 3733–3741 (2004).
Lawrence, M.C. et al. Structure of the haemagglutinin-neuraminidase from human parainfluenza virus type III. J. Mol. Biol. 335, 1343–1357 (2004).
Navaratnarajah, C.K. et al. Dynamic interaction of the measles virus hemagglutinin with its receptor signaling lymphocytic activation molecule (SLAM, CD150). J. Biol. Chem. 283, 11763–11771 (2008).
Hu, A., Sheshberadaran, H., Norrby, E. & Kovamees, J. Molecular characterization of epitopes on the measles virus hemagglutinin protein. Virology 192, 351–354 (1993).
Fournier, P. et al. Antibodies to a new linear site at the topographical or functional interface between the haemagglutinin and fusion proteins protect against measles encephalitis. J. Gen. Virol. 78, 1295–1302 (1997).
Ertl, O.T., Wenz, D.C., Bouche, F.B., Berbers, G.A. & Muller, C.P. Immunodominant domains of the Measles virus hemagglutinin protein eliciting a neutralizing human B cell response. Arch. Virol. 148, 2195–2206 (2003).
Ruigrok, R.W. & Gerlier, D. Structure of the measles virus H glycoprotein sheds light on an efficient vaccine. Proc. Natl. Acad. Sci. USA 104, 20639–20640 (2007).
Bossart, K.N. et al. Receptor binding, fusion inhibition, and induction of cross-reactive neutralizing antibodies by a soluble G glycoprotein of Hendra virus. J. Virol. 79, 6690–6702 (2005).
Yuan, P., Leser, G.P., Demeler, B., Lamb, R.A. & Jardetzky, T.S. Domain architecture and oligomerization properties of the paramyxovirus PIV 5 hemagglutinin-neuraminidase (HN) protein. Virology 378, 282–291 (2008).
Chothia, C. & Jones, E.Y. The molecular structure of cell adhesion molecules. Annu. Rev. Biochem. 66, 823–862 (1997).
Cao, E. et al. NTB-A receptor crystal structure: insights into homophilic interactions in the signaling lymphocytic activation molecule receptor family. Immunity 25, 559–570 (2006).
Paal, T. et al. Probing the spatial organization of measles virus fusion complexes. J. Virol. 83, 10480–10493 (2009).
Radecke, F. et al. Rescue of measles viruses from cloned DNA. EMBO J. 14, 5773–5784 (1995).
Takeda, M. et al. Long untranslated regions of the measles virus M and F genes control virus replication and cytopathogenicity. J. Virol. 79, 14346–14354 (2005).
Adachi, H. et al. Application of a two-liquid system to sitting-drop vapour-diffusion protein crystallization. Acta Crystallogr. D Biol. Crystallogr. 59, 194–196 (2003).
Acknowledgements
We thank the beamline staff of Photon Factory (Tsukuba, Japan) and SPring8 (Hyogo, Japan) for technical help during data collection. We also thank M.A. Billeter (Institute of Molecular Biology, University of Zürich) for reagents, M. Takeda, I. Tanaka, K. Inaba, K. Mihara, T. Oka, H. Aramaki, K. Tokunaga, M. Kajikawa, K. Kuroki and K. Sasaki for discussion and E.O. Saphire for reviewing the manuscript. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Ministry of Health, Labor and Welfare of Japan. T.H. is supported by the Japan Society for the Promotion of Science Research Fellowship for Young Scientists.
Author information
Authors and Affiliations
Contributions
T.H., K.M. and Y.Y. designed the research; T.H. and J.K. prepared and crystallized MV-H–SLAM complexes; T.H. and M.K. carried out binding, BN-PAGE and measles virus infection assays; T.H., T.O., N.M. and K.M. determined the crystal structures; T.H., K.M. and Y.Y. wrote the paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 and Supplementary Methods (PDF 7278 kb)
Rights and permissions
About this article
Cite this article
Hashiguchi, T., Ose, T., Kubota, M. et al. Structure of the measles virus hemagglutinin bound to its cellular receptor SLAM. Nat Struct Mol Biol 18, 135–141 (2011). https://doi.org/10.1038/nsmb.1969
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nsmb.1969
This article is cited by
-
Metagenomics-enabled reverse-genetics assembly and characterization of myotis bat morbillivirus
Nature Microbiology (2023)
-
A defined anthocyanin mixture sourced from bilberry and black currant inhibits Measles virus and various herpesviruses
BMC Complementary Medicine and Therapies (2022)
-
Neuropathologic and molecular aspects of a canine distemper epizootic in red foxes in Germany
Scientific Reports (2022)
-
Biophysical research in Hokkaido University, Japan
Biophysical Reviews (2020)
-
Tropism and molecular pathogenesis of canine distemper virus
Virology Journal (2019)