The Role of Charge and Multiple Faces of the CD8α/α Homodimer in Binding to Major Histocompatibility Complex Class I Molecules: Support for a Bivalent Model

The CD8 dimer interacts with the α 3 domain of major histocompatibility complex class I molecules through two immunoglobulin variable-like domains. In this study a crystal structure-informed mutational analysis has been performed to identify amino acids in the CD8α/α homodimer that are likely to be involved in binding to class I. Several key residues are situated on the top face of the dimer within loops analogous to the complementarity-determining regions (CDRs) of immunoglobulin. In addition, other important amino acids are located in the A and B β-strands on the sides of the dimer. The potential involvement of amino acids on both the top and the side faces of the molecule is consistent with a bivalent model for the interaction between a single CD8α/α homodimer and two class I molecules and may have important implications for signal transduction in class I-expressing cells. This study also demonstrates a role for the positive surface potential of CD8 in class I binding and complements previous work demonstrating the importance of a negatively charged loop on the α 3 domain of class I for CD8α/α-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the α 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B β-strands contact the α 2 domain of class I.