Structural basis for NKG2A/CD94 recognition of HLA-E.

Area of Science:

• Immunology
• Structural Biology
• Evolutionary Biology

Background:

• Natural killer (NK) cell receptors NKG2x/CD94 are crucial for immunosurveillance.
• They bind HLA-E, which presents peptides from MHC class I leader sequences, monitoring MHC class I expression.
• This interaction is key to distinguishing self from non-self.

Purpose of the Study:

• To determine the crystal structure of the NKG2A/CD94/HLA-E complex.
• To elucidate the molecular basis for differential affinities between NKG2A/CD94 and NKG2C/CD94.
• To investigate the evolutionary pressures on the NKG2x/CD94 receptor family.

Main Methods:

• X-ray crystallography to determine the structure of the NKG2A/CD94/HLA-E complex.
• Biochemical assays to assess receptor-ligand binding affinities.
• Comparative evolutionary analysis across primate species.

Main Results:

• The crystal structure revealed that the variable C-terminal peptide region interacts with CD94.
• Specific residues (167-170) in NKG2A/C, at the CD94 interface, confer higher affinity to NKG2A/CD94.
• Evolutionary analysis showed positive selection on NKG2A and NKG2C, particularly at the CD94 interface.
• NKG2C/CD94, but not NKG2A/CD94, weakly binds the cytomegalovirus (CMV) UL18.

Conclusions:

• The NKG2A/CD94/HLA-E structure highlights the roles of CD94 and specific NKG2A/C residues in ligand binding and affinity.
• Positive selection on NKG2A and NKG2C suggests adaptation to pathogen-derived ligands.
• The differential binding to UL18 indicates a mechanism for avoiding pathogen subversion, shaping receptor evolution.