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The NK Cell MHC Class I Receptor Ly49A Detects Mutations on H-2D^d Inside and Outside of the Peptide Binding Groove¹

Naoki Matsumoto^2,*,, Wayne M. Yokoyama, Somei Kojima and Kazuo Yamamoto^*

^* Laboratory of Molecular Medicine, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan; Department of Parasitology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

The NK cell inhibitory receptor Ly49A recognizes the mouse MHC class I molecule H-2D^d and participates in the recognition of missing self. Previous studies indicated that the determinant recognized by Ly49A exists in 1/2 domain of H-2D^d. Here we have substituted polymorphic as well as conserved residues of H-2D^d 1/2 domain (when compared with H-2K^d, which does not interact with Ly49A). We then tested the ability of the H-2D^d mutants to interact with Ly49A by soluble Ly49A tetramer binding and NK cell cytotoxicity inhibition assays. Individual introduction of mutations converting the H-2D^d residue into the corresponding H-2K^d residue (N30D, D77S, or A99F) in H-2D^d partially abrogated the interaction between Ly49A and H-2D^d. Introduction of the three mutations into H-2D^d completely abolished Ly49A recognition. Individual introduction of D29N or R35A mutation into the residues of H-2D^d that are conserved among murine MHC class I severely impaired the interaction. The crystal structure of H-2D^d reveals that D77 and A99 are located in the peptide binding groove and that N30, D29, and R35 are in the interface of the three structural domains of MHC class I: 1/2, 3, and ₂-microglobulin. These data suggest that Ly49A can monitor mutations in MHC class I inside and outside of the peptide binding groove and imply that inhibitory MHC class I-specific receptors are sensitive to mutations in MHC class I as well as global loss of MHC class I. Our results also provide insight into the molecular basis of Ly49A to distinguish MHC class I polymorphism.

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