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Targeting of a natural killer cell receptor family by a viral immunoevasin

Nature Immunology volume 14, pages 699–705 (2013)Cite this article

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Abstract

Activating and inhibitory receptors on natural killer (NK) cells have a crucial role in innate immunity, although the basis of the engagement of activating NK cell receptors is unclear. The activating receptor Ly49H confers resistance to infection with murine cytomegalovirus by binding to the 'immunoevasin' m157. We found that m157 bound to the helical stalk of Ly49H, whereby two m157 monomers engaged the Ly49H dimer. The helical stalks of Ly49H lay centrally across the m157 platform, whereas its lectin domain was not required for recognition. Instead, m157 targeted an 'aromatic peg motif' present in stalks of both activating and inhibitory receptors of the Ly49 family, and substitution of this motif abrogated binding. Furthermore, ligation of m157 to Ly49H or Ly49C resulted in intracellular signaling. Accordingly, m157 has evolved to 'tackle the legs' of a family of NK cell receptors.

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Figure 1: Ly49-m157 interaction.
Figure 2: Docking of Ly49 on MHC class I and m157.
Figure 3: Structure of Ly49H NKD-α3s bound to m157.
Figure 4: Binding of mutant receptors of the Ly49 family to m157G1F.
Figure 5: Possible Ly49-MHC-m157 interactions at the cell surface.
Figure 6: Functional recognition of m157 by inhibitory and activating Ly49 receptors.

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Acknowledgements

We thank the staff of the crystallization facility of Monash University for assistance; A. Shahine, R. Koh, M. Peverelli and I. Larma for technical assistance; S. Lemieux (Institut Armand-Frappier) for the 4LO3311 hybridoma; and W. Yokoyama (Washington University) for BWZ HD12 and BWZ DAP12 cells and the 3D10 hybridoma. This research was undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia. Supported by the National Health and Medical Research Council of Australia (M.J.C., R.B., L.C.S., J.D.C. and J.R.), Australian Research Council (M.A.P., M.J.C. and J.P.V.) and Pfizer Australia (T.B.).

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Author notes

  1. Travis Beddoe, Andrew G Brooks and Jamie Rossjohn: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

    Richard Berry, Natasha Ng, Julian P Vivian, Felix A Deuss, Adrian D McAlister, Travis Beddoe & Jamie Rossjohn

  2. Department of Microbiology & Immunology, University of Melbourne, Parkville, Australia

    Philippa M Saunders, Jie Lin, Alexandra J Corbett, Jacqueline M Widjaja, Lucy C Sullivan & Andrew G Brooks

  3. Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Australia

    Catherine A Forbes, Anthony A Scalzo, Mariapia A Degli-Esposti & Jerome D Coudert

  4. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Australia

    Catherine A Forbes, Anthony A Scalzo, Mariapia A Degli-Esposti & Jerome D Coudert

  5. Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia

    Matthew A Perugini

  6. Structural Biology Division, Walter and Eliza Hall Institute, University of Melbourne, Parkville, Australia

    Melissa J Call

  7. Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, UK

    Jamie Rossjohn

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  1. Richard Berry
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Contributions

R.B. solved the structure, undertook analysis, designed, did and interpreted experiments and contributed to the writing of the manuscript; N.N., P.M.S., J.P.V., J.L., F.A.D., A.J.C., C.A.F., J.M.W., L.C.S., A.D.M., M.A.P., M.J.C., A.A.S. and M.A.D.-E. provided reagents, did experiments and/or contributed to the writing of the manuscript; J.D.C. designed, undertook and analyzed the signaling experiments and contributed to the writing of the manuscript; and T.B., A.G.B. and J.R. contributed to the design and interpretation of experiments, project management and the writing of the manuscript.

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Correspondence to Travis Beddoe, Andrew G Brooks or Jamie Rossjohn.

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Berry, R., Ng, N., Saunders, P. et al. Targeting of a natural killer cell receptor family by a viral immunoevasin. Nat Immunol 14, 699–705 (2013). https://doi.org/10.1038/ni.2605

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