The Journal of Experimental Medicine
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Published online March 10, 2008
doi:10.1084/jem.20072525
The Journal of Experimental Medicine, Vol. 205, No. 3, 725-735
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Petrie et al.
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ARTICLE

 CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

Emma J. Petrie1, Craig S. Clements1, Jie Lin2, Lucy C. Sullivan2, Darryl Johnson2, Trevor Huyton1, Annie Heroux3, Hilary L. Hoare1, Travis Beddoe1, Hugh H. Reid1, Matthew C.J. Wilce1, Andrew G. Brooks2, and Jamie Rossjohn1

1 The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia
2 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia
3 Biology Department, Brookhaven National Laboratory, Upton, NY 11973

CORRESPONDENCE Jamie Rossjohn: jamie.rossjohn{at}med.monash.edu.au OR Andrew G. Brooks: agbrooks{at}unimelb.edu.au

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A–HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor–ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.

Abbreviations used: BSA, buried surface area; KIR, killer cell Ig-like receptor; SC, shape complementarity; VDW, van der Waals.

Emma J. Petrie and Craig S. Clements contributed equally to this work.

Andrew G. Brooks and Jamie Rossjohn contributed equally to this work.


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