NOVEL STRUCTURAL FEATURES OF THE HUMAN HISTOCOMPATIBILITY MOLECULES HLA-DQ AS REVEALED BY MODELING BASED ON THE PUBLISHED STRUCTURE OF THE RELATED MOLECULE HLA-DR

Structural modeling of the HLA-DQ molecules, a group of human histocom patibility antigens linked to autoimmune diseases and immunosuppressio n-based on the structure of the homologous molecule DR1, has revealed an overall shape typical of the class II histocompatibility molecules, yet with several novel features, These are unique to HLA-DQ and inclu de: (1) an antigen-binding groove with a polymorphic first pocket and anchoring in the second and/or fifth pocket, (2) a polymorphic beta 49 -56 dimerization patch, and (3) in many alleles a prominent Arg-Gly-As p loop (beta 167-169), probably involved in cell adhesion, as it exhib its an architecture similar to identical sequences involved in such fu nction, The alpha 2 beta 2 dimerisation domain and the CD4-binding reg ion are nearly identical to their counterparts in the structure of HLA -DR1. The significance of the few substitutions in the CD-4 binding re gion remains to be evaluated, The polymorphic first antigen-binding po cket and the anchoring in the second and/or fifth pocket point to diff erences in antigenic fragment selection compared to HLA-DR antigens, w hile the polymorphism in the beta 49-56 homodimerization patch implies either ease of spontaneous or T lymphocyte receptor-induced homodimer ization or difficulty in the latter, As homodimerization appears to be an obligatatory intermediate in the activation of cognate DQ-restrict ed T lymphocytes and DQ-bearing antigen-presenting cells, the dimeriza tion properties of DQ allels signify the respective ease or difficulty of activation of these two cell types, The RGD loop confers cell adhe sion possibilities to those DQ allels that possess it, yet its putativ e ligand cannot be defined at present. These features are suggestive o f the probable mechanisms through which some of the unique immunologic al properties of the HLA-DB molecules are effected. (C) 1996 Academic Press, Inc.