A small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Ac1-11.
The N-terminal peptide Ac1-11 of myelin basic protein induces experimental autoimmune encephalomyelitis in H-2(u) and (H-2(u) x H-2(s)) mice but does not in H-2(s) mice. Ac1-11 binds weakly to the class II major histocompatibility complex (MHC) molecule I-Au but not at all to I-As. We have studied the interaction of Ac1-11 and I-Au as a model system for therapeutic intervention in the autoimmune response seen in experimental autoimmune encephalomyelitis. Two polymorphic residues that differ between I-Au and I-As, Y26beta and T28beta, and one conserved residue, E74beta, confer specific binding of Ac1-11 to I-Au. A fourth residue, R70beta in I-Au, affects both peptide binding and T cell recognition. These results are consistent with a model that places arginine at position five of Ac1-11 in pockets 4 and 7 of the MHC groove, which is formed in part by residues 26, 28, 70, and 74 of Abetau and places lysine at position four of Ac1-11, previously shown to be a major MHC contact, in hydrophobic pocket 6. The data indicate that the primary region of I-Au that confers specific binding of Ac1-11 lies in the center of the peptide binding groove rather than in the region that contacts the N terminus of the peptide, as has been shown for HLA DR and the homologous I-E molecules.
Pearson
C I
CI
Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, CA 94305, USA.
Gautam
A M
AM
Rulifson
I C
IC
Liblau
R S
RS
McDevitt
H O
HO
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D004676:Myelin Basic Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D006683:HLA-DQ Antigens; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments