The Journal of Experimental Medicine
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Published online 15 January 2001.
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© The Rockefeller University Press, 0022-1007/2001/1/147/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 2, January 15, 2001 147-158

Original Article

The Functional Binding Site for the C-Type Lectin–Like Natural Killer Cell Receptor Ly49a Spans Three Domains of Its Major Histocompatibility Complex Class I Ligand

Naoki Matsumotoa, Motoaki Mitsukia, Kyoko Tajimaa, Wayne M. Yokoyamab, and Kazuo Yamamotoa

a Laboratory of Molecular Medicine, Department of Integrated Biosciences, The University of Tokyo Graduate School of Frontier Sciences, Tokyo 113-0033, Japan
b Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110
Laboratory of Molecular Medicine, Department of Integrated Biosciences, The University of Tokyo Graduate School of Frontier Sciences, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.81-3-5841-892381-3-5841-8785

nmatsu{at}k.u-tokyo.ac.jp

Natural killer (NK) cells express receptors that recognize major histocompatibility complex (MHC) class I molecules and regulate cytotoxicity of target cells. In this study, we demonstrate that Ly49A, a prototypical C-type lectin–like receptor expressed on mouse NK cells, requires species-specific determinants on β2-microglobulin (β2m) to recognize its mouse MHC class I ligand, H-2Dd. The involvement of β2m in the interaction between Ly49A and H-2Dd is also demonstrated by the functional effects of a β2m-specific antibody. We also define three residues in {alpha}1/{alpha}2 and {alpha}3 domains of H-2Dd that are critical for the recognition of H-2Dd on target cells by Ly49A. In the crystal structure of the Ly49A/H-2Dd complex, these residues are involved in hydrogen bonding to Ly49A in one of the two potential Ly49A binding sites on H-2Dd. These data unambiguously indicate that the functional effect of Ly49A as an MHC class I–specific NK cell receptor is mediated by binding to a concave region formed by three structural domains of H-2Dd, which partially overlaps the CD8 binding site.

Key Words: β2-microglobulin • inhibitory receptor • cytotoxicity • mutation • H-2 antigens

Abbreviations used in this paper: ADCC, antibody-dependent cellular cytotoxicity; β2m, β2-microglobulin; CHO, Chinese hamster ovary; MFI, mean fluorescence intensity; sLy49A, soluble Ly49A.

N. Matsumoto and M. Mitsuki contributed equally to this work.

© 2001 The Rockefeller University Press


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