Projects per year
Abstract
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-2Kb/H-2Dd, 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-2Kb. Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2Kb 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.
Original language | English |
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Pages (from-to) | 18740-18752 |
Number of pages | 13 |
Journal | Journal of Biological Chemistry |
Volume | 291 |
Issue number | 36 |
DOIs | |
Publication status | Published - 2 Sept 2016 |
Keywords
- crystal structure
- innate immunity
- major histocompatibility complex (MHC)
- natural killer cells (NK cells)
- receptor structure-function
Projects
- 1 Finished
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ARC Centre of Excellence in Advanced Molecular Imaging
Whisstock, J., Abbey, B., Nugent, K., Quiney, H. M., Godfrey, D. I., Heath, W., Fairlie, D., Chapman, H., Peele, A., Davey, J. & Wittmann, A.
30/06/14 → 31/03/21
Project: Research
Equipment
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Australian Synchrotron
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility
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Macromolecular Crystallisation Facility
Geoffrey Kong (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility