title: Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2.
abstract: The dimeric cell-surface glycoprotein CD8 is crucial to the positive selection of cytotoxic T cells in the thymus. The homodimer CD8alpha(alpha) or the heterodimer alpha beta stabilizes the interaction of the T-cell antigen receptor (TCR) with major histocompatibility complex (MHC) class I/peptide by binding to the class I molecule. Here we report the crystal structure at 2.7 A resolution of a complex between CD8alpha(alpha) and the human MHC molecule HLA-A2, which is associated with peptide. CD8alpha(alpha) binds one HLA-A2/peptide molecule, interfacing with the alpha2 and alpha3 domains of HLA-A2 and also contacting beta2-microglobulin. A flexible loop of the alpha3 domain (residues 223-229) is clamped between the complementarity-determining region (CDR)-like loops of the two CD8 subunits in the classic manner of an antibody-antigen interaction, precluding the binding of a second MHC molecule. The position of the alpha3 domain is different from that in uncomplexed HLA-A2, being most similar to that in the TCR/Tax/HLA-A2 complex, but no conformational change extends to the MHC/peptide surface presented for TCR recognition. Although these shifts in alpha3 may provide a synergistic modulation of affinity, the binding of CD8 to MHC is clearly consistent with an avidity-based contribution from CD8 to TCR-peptide-MHC interactions.
authors.affiliation: Molecular Immunology Group, Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
authors.forename: G F
authors.initials: GF
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: Tormo
authors.forename: U C
authors.initials: UC
authors.lastname: Gerth
authors.forename: J R
authors.initials: JR
authors.lastname: Wyer
authors.forename: A J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: D I
authors.initials: DI
authors.lastname: Stuart
authors.forename: J I
authors.initials: JI
authors.lastname: Bell
authors.forename: E Y
authors.initials: EY
authors.lastname: Jones
authors.forename: B K
authors.initials: BK
authors.lastname: Jakobsen
mesh_terms: D016827:CD8 Antigens / Q000737:chemistry* / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D016827:CD8 Antigens; D015789:HLA-A2 Antigen; D011994:Recombinant Proteins