Binding of the Natural Killer Cell Inhibitory Receptor Ly49A to Its Major Histocompatibility Complex Class I Ligand

Abstract

Ly49A, an inhibitory C-type lectin-like mouse natural killer cell receptor, functions through interaction with the major histocompatibility complex class I molecule, H-2Dd. The x-ray crystal structure of the Ly49A[]H-2Dd complex revealed that homodimeric Ly49A interacts at two distinct sites of H-2Dd: Site 1, spanning one side of the []1 and []2 helices, and Site 2, involving the []1, []2, []3, and []2 m domains. Mutants of Ly49A, H-2Dd , and []2 -mi- croglobulin 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-2Dd interaction, with no effect on gross structure or T cell receptor interaction. The region sur- rounding the most critical residues (in H-2Dd, Asp122; in Ly49A, Asp229, Ser236, Thr238, Arg239, and Asp241; and in 􏰊2-microglobulin, Gln29 and Lys58) of the Ly49A[]H-2Dd interface at Site 2 includes a network of water mole- cules, suggesting a molecular basis for allelic specificity in natural killer cell recognition.