How does the HLA protein bind its peptide antigen?
HLA proteins comprise two α-helical walls with a β-pleated sheet forming the floor of the binding site. In MHC class II molecules, the α- and β-chains together form this structure, whereas in MHC class I molecules, only the α-chain contributes to the peptide antigen-binding site.
The antigen binds at points on both the α-helical walls and the β-pleated floor. The three areas of greatest genetic diversity (hypervariable regions) are expressed in segments of each of the α-helices and β-pleated sheet. This genetic variation very specifically affects or “selects” which antigens can bind to specific molecules. In addition, it specifically “selects” which TCRs can interact with specific combinations of MHC-antigen complex.