National Center for
5J6H: Recognition Of The Mhc Class Ib Molecule H2-q10 By The Natural Killer Cell Receptor Ly49c
Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C
J. Biol. Chem. (2016) 291 p.18740-18752
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 ( approximately 5 mum) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both approximately 1 mum), 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 alpha1, alpha2, and alpha3 domains, as well as the associated beta2-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 beta4-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.