Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C

J Biol Chem. 2016 Sep 2;291(36):18740-52. doi: 10.1074/jbc.M116.737130. Epub 2016 Jul 6.


Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules.

Keywords: crystal structure; innate immunity; major histocompatibility complex (MHC); natural killer cells (NK cells); receptor structure-function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • H-2 Antigens / chemistry
  • H-2 Antigens / genetics
  • H-2 Antigens / immunology
  • Histocompatibility Antigen H-2D / chemistry*
  • Histocompatibility Antigen H-2D / genetics
  • Histocompatibility Antigen H-2D / immunology
  • Killer Cells, Natural / chemistry*
  • Killer Cells, Natural / immunology
  • Mice
  • Mice, Knockout
  • NK Cell Lectin-Like Receptor Subfamily A / chemistry*
  • NK Cell Lectin-Like Receptor Subfamily A / genetics
  • NK Cell Lectin-Like Receptor Subfamily A / immunology
  • Protein Domains
  • Protein Structure, Quaternary


  • H-2 Antigens
  • H-2Kb protein, mouse
  • Histocompatibility Antigen H-2D
  • Klra3 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily A

Associated data

  • PDB/1YN6
  • PDB/3C8J
  • PDB/3C8K