title: The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model.
abstract: The CD8 dimer interacts with the alpha 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 CD8 alpha/alpha 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 beta-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 CD8 alpha/alpha 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 alpha 3 domain of class I for CD8 alpha/alpha-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the alpha 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B beta-strands contact the alpha 2 domain of class I.
authors.affiliation: Section of Immunobiology, Yale University, New Haven, CT 06520-8035.
authors.forename: P A
authors.initials: PA
authors.lastname: Giblin
authors.forename: D J
authors.initials: DJ
authors.lastname: Leahy
authors.forename: J
authors.initials: J
authors.lastname: Mennone
authors.forename: P B
authors.initials: PB
authors.lastname: Kavathas
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001665:Binding Sites; D016827:CD8 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D004563:Electrochemistry; D006680:HLA Antigens / Q000737:chemistry / Q000378:metabolism; D000882:Haplorhini; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D016827:CD8 Antigens; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I