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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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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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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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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DOI: https://doi.org/10.1038/ni.2605
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