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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 5; pp. 1716 - 1720
• Main Authors: Giblin, Patricia A., Leahy, Daniel J., Mennone, John, Kavathas, Paula B.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01-03-1994; National Acad Sciences
• Subjects: Amino acids; Analytical, structural and metabolic biochemistry; Animals; B-Lymphocytes - immunology; Binding Sites; Biological and medical sciences; CD8 Antigens - chemistry; CD8 Antigens - genetics; CD8 Antigens - metabolism; Cell Adhesion - immunology; Cell Line; COS cells; Crystal structure; Dimers; Electrochemistry; Fundamental and applied biological sciences. Psychology; Glycoproteins; Haplorhini; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - metabolism; HLA Antigens - chemistry; HLA Antigens - metabolism; Humans; Immunoglobulins; Models, Molecular; Molecular interactions; Molecules; Monomers; Mutagenesis, Site-Directed; Protein Binding; Protein Conformation; Proteins; T lymphocytes; Human; Domain structure; Major histocompatibility system; T-Lymphocyte; Biological marker; Alpha-Peptide chain; Molecular interaction; Dimer; Glycoproteins; Models; Class I histocompatibility antigen
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.5.1716

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.