The Journal of Experimental Medicine
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Published online 8 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

Correspondence to: Naoki Matsumoto, 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. Tel:81-3-5841-8785 Fax:81-3-5841-8923 E-mail: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 ß2-microglobulin (ß2m) to recognize its mouse MHC class I ligand, H-2Dd. The involvement of ß2m in the interaction between Ly49A and H-2Dd is also demonstrated by the functional effects of a ß2m-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: ß2-microglobulin, inhibitory receptor, cytotoxicity, mutation, H-2 antigens


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