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J. Biol. Chem., Vol. 277, Issue 2, 1433-1442, January 11, 2002

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Binding of the Natural Killer Cell Inhibitory Receptor Ly49A to Its Major Histocompatibility Complex Class I Ligand
CRUCIAL CONTACTS INCLUDE BOTH H-2D^d AND ₂-MICROGLOBULIN^*

Jian Wang, Mary C. Whitman, Kannan Natarajan, José Tormo^§, Roy A. Mariuzza^¶, and David H. Margulies

From the  Molecular Biology Section, Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-1892, ^§ Campus de la Universidad Autonoma de Madrid, 28049 Madrid, Spain, and ^¶ Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850

Ly49A, an inhibitory C-type lectin-like mouse natural killer cell receptor, functions through interaction with the major histocompatibility complex class I molecule, H-2D^d. The x-ray crystal structure of the Ly49A·H-2D^d complex revealed that homodimeric Ly49A interacts at two distinct sites of H-2D^d: Site 1, spanning one side of the 1 and 2 helices, and Site 2, involving the 1, 2, 3, and ₂m domains. Mutants of Ly49A, H-2D^d, and ₂-microglobulin at intermolecular contacts and the Ly49A dimer interface were examined for binding affinity and kinetics. Although mutations at Site 1 had little affect, several at Site 2 and at the dimer interface hampered the Ly49A·H-2D^d interaction, with no effect on gross structure or T cell receptor interaction. The region surrounding the most critical residues (in H-2D^d, Asp¹²²; in Ly49A, Asp²²⁹, Ser²³⁶, Thr²³⁸, Arg²³⁹, and Asp²⁴¹; and in ₂-microglobulin, Gln²⁹ and Lys⁵⁸) of the Ly49A·H-2D^d interface at Site 2 includes a network of water molecules, suggesting a molecular basis for allelic specificity in natural killer cell recognition.

This paper is dedicated to the memory of José Tormo, colleague and friend.

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