Journal of Molecular Biology
Volume 377, Issue 5, 11 April 2008, Pages 1297-1303
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Subtle Changes in Peptide Conformation Profoundly Affect Recognition of the Non-Classical MHC Class I Molecule HLA-E by the CD94–NKG2 Natural Killer Cell Receptors

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Abstract

Human leukocyte antigen (HLA)-E is a non-classical major histocompatibility complex class I molecule that binds peptides derived from the leader sequences of other HLA class I molecules. Natural killer cell recognition of these HLA-E molecules, via the CD94–NKG2 natural killer family, represents a central innate mechanism for monitoring major histocompatibility complex expression levels within a cell. The leader sequence-derived peptides bound to HLA-E exhibit very limited polymorphism, yet subtle differences affect the recognition of HLA-E by the CD94–NKG2 receptors. To better understand the basis for this peptide-specific recognition, we determined the structure of HLA-E in complex with two leader peptides, namely, HLA-Cw*07 (VMAPRALLL), which is poorly recognised by CD94–NKG2 receptors, and HLA-G*01 (VMAPRTLFL), a high-affinity ligand of CD94–NKG2 receptors. A comparison of these structures, both of which were determined to 2.5-Å resolution, revealed that allotypic variations in the bound leader sequences do not result in conformational changes in the HLA-E heavy chain, although subtle changes in the conformation of the peptide within the binding groove of HLA-E were evident. Accordingly, our data indicate that the CD94–NKG2 receptors interact with HLA-E in a manner that maximises the ability of the receptors to discriminate between subtle changes in both the sequence and conformation of peptides bound to HLA-E.

Section snippets

Structural determination and analysis of HLA-E/peptide complexes

Previous studies have shown that substitutions at P6 and P8 of the HLA-E peptide have a direct effect on the affinity of the interaction between CD94–NKG2A and HLA-E.15, 17, 18 To better understand the structural basis for the observed peptide-dependent differences in the affinity of CD94–NKG2 receptors for HLA-E, we determined the crystal structure of HLA-E in complex with the HLA-G*01 leader sequence peptide (VMAPRTLFL, HLA-EVMAPRTLFL), which interacted with the CD94–NKG2 receptors with the

Acknowledgements

The National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC) supported this work. L.S. and T.B. are supported by a Peter Doherty NHMRC Fellowship and NHMRC and Career Development Award, respectively. C.S.C. is supported by an ARC Queen Elizabeth II Fellowship, and J.R. is supported by an ARC Federation Fellowship. We thank the staff at BioCars for their assistance with data collection.

References (30)

  • S. Lazetic et al.

    Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits

    J. Immunol.

    (1996)
  • K. Natarajan et al.

    Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination

    Annu. Rev. Immunol.

    (2002)
  • T. Bellon et al.

    Triggering of effector functions on a CD8+ T cell clone upon the aggregation of an activatory CD94/kp39 heterodimer

    J. Immunol.

    (1999)
  • A.G. Brooks et al.

    NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor

    J. Exp. Med.

    (1997)
  • F. Borrego et al.

    Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis

    J. Exp. Med.

    (1998)
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    H.L.H. and L.C.S. contributed equally to this work.

    A.G.B. and J.R. are the senior authors of this work.

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