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Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors

Nature volume 389, pages 96–100 (1997)Cite this article

An Erratum to this article was published on 20 November 1997

Abnormal cells deficient in class I major histocompatibility complex (MHC) expression are lysed by a class of lymphocytes called natural killer (NK) cells1. This lysis provides a defence against pathogens and tumour cells that downregulate MHC expression to avoid an MHC-restricted, T-cell immune response. Normal cells escape lysis because their MHC molecules are recognized by NK-cell inhibitory receptors, which inhibit lysis2. Several such inhibitory receptor families have been described in humans and mice (reviewed in ref. 2). In the human killer-cell inhibitory receptor family, individual p58 members are specific for a subset of class I human leukocyte antigen (HLA)-C molecules. The human p58 natural killer-cell inhibitory receptor clone 42 recognizes HLA-Cw4, -Cw2 and -Cw6, but not HLA-Cw3, -Cw2, -Cw7 or -Cw8, which are recognized by p58 killer-cell inhibitor receptor clone 43 (ref. 3). We have determined the X-ray structure of the p58 NK-cell inhibitory receptor clone 42 at 1.7-Å resolution. The structure has tandem immunoglobulin-like domains positioned at an acute, 60-degree angle. Loops on the outside of the elbow between the domains form a binding site projected away from the NK-cell surface. The topology of the domains and their arrangement relative to each other reveal a relationship to the haematopoietic receptor family, with implications for the signalling mechanism in NK cells.

The topology of the D1 immunoglobulin-like domain is of the h-type6, similar to that of the D1 domains of the human growth hormone receptor (hGHR)7, human prolactin receptor (hPLR)7, and the erythropoietin receptor (EPOR)8. The D2 domain has the closely related s-type topology6 found in the D2 domains of hGHR, hPLR and EPOR8,9,10, and both domains of class II receptors of the haematopoietic superfamily, including the α-chain of the interferon-γ receptor (IFN-γRα)11, and tissue factor12,13. The s-type topology has also been found in other two-domain structures, including the co-receptor CD4 (refs 14, 15), the cell-adhesion molecule CD2 (ref. 16) and neuroglian17. However, in both CD2 and CD4, the s-type domain is paired in tandem with a variable-type immunoglobulin domain and the two domains assume a linear conformation, lacking the elbow region found in all of the haematopoietic receptors and KIR. Although some members of the haematopoietic receptor superfamily contain additional domains, ligand binding is mediated through the h- or s-type domains7. The s-type topology of D2 has a β-sheet of three strands, A, B and E (Fig. 1a, b, dark orange) packed against a β-sheet of four strands, C′, C, F and G (Fig. 1a, b, light orange). In h-type topology of the D1 domain, the C′ strand is elongated, pairing first with the C strand of the C′CFG β-sheet and at its far end (where it is renamed D) pairing with the E strand of the ABE(D) β-sheet (Fig. 1a, b). The switch from one β-sheet to the other occurs at a kink in strand C′/D at Gly 53. When superimposed, the D1 and D2 domains, which have 40% sequence identity, are strikingly similar in structure with a root-mean-square (r.m.s.) deviation of 0.9 Å for 85 Cα pairs.

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Figure 1: Structure and topology of p58-cl42 KIR.
Figure 2: Structure and topology of p58-cl42 KIR.
Figure 3: The interdomain interface defines a 60-deg angle and the interdomain elbow is a ligand-binding site.
Figure 4: The interdomain interface defines a 60-deg angle and the interdomain elbow is a ligand-binding site.
Figure 5: Comparison of the KIR and haematopoietic receptor family structures.
Figure 6: Comparison of the KIR and haematopoietic receptor family structures.
Figure 7: Electron-density maps showing the refined model in the region of the WSKSS sequence.

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Acknowledgements

We thank D. N. Garboczi, X. D. Zhang, P. Rosenthal, K. Smith and L. Chen for help with data collection R. Hellmiss for preparing Fig. 1b W. I. Weis and V. Ramakrishnan for discussion Y. Liu for the program for calculating f ′and f′ values W. Kossiakoff for the coordinates of the hPLR–hGH complex Harvard microchemistry facility for mass spectroscopy A. Haykov and R. Crouse for technical support the staff at the Brookhaven X25 beamline and CHESS for assistance with data collection and D. N. Garboczi for reading the manuscript. Q.R.F. is a recipient of an NSF predoctoral fellowship. L. M. is an associate and D. C. W. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Christine C. Winter, Nicolai Wagtmann and Eric O. Long: These authors contributed equally to this work.

  2. Don C.Wiley and : Correspondence and requests for materials should be addressed to D.C.W. Coordinates will be deposited in the Brookhaven Data base and are available now from Q.R.F.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, 7 Divinity Avenue, Cambridge, 02138, Massachusetts, USA

    Qing R. Fan & Lidia Mosyak

  2. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, 20852, Maryland, USA

    Qing R. Fan & Lidia Mosyak

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Fan, Q., Mosyak, L., Winter, C. et al. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature 389, 96–100 (1997). https://doi.org/10.1038/38028

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